Transcriptomic landscape of Pituitary Adenomas: potential diagnostic and therapeutic targets

Transcriptomic landscape of Pituitary Adenomas: potential diagnostic and therapeutic targets | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Transcriptomic landscape of Pituitary Adenomas: potential diagnostic and therapeutic targets Maryam Honardoost, Yousof Bavafa Shandiz, Nazanin Hosseinkhan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7604876/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Pituitary adenomas (PAs) account for 10–15% of intracranial neoplasms. Although generally benign, many PAs, especially non-functional types lack effective medical treatments. Cell membrane proteins are promising targets for diagnosis and therapy due to their accessibility and specificity. This study aimed to identify shared and subtype-specific deregulated membrane proteins across PA types and evaluate the potential of natural compounds and small molecules to inhibit these targets. Methods Eight microarray datasets comprising 77 PA and 25 normal pituitary samples were analyzed using the Limma package in R version 4.3.0. Batch effects were removed with ComBat. Differentially expressed genes (DEGs) were identified and filtered for membrane proteins. Functional annotation was performed using EnrichR. Structures of key proteins were retrieved from PDB/AlphaFold and docked with plant-derived compounds and small molecules using PyRx. Results FILIP1L (upregulated) and ISRL (downregulated) were identified as shared membrane protein targets across all PA subtypes. Subtype-specific upregulated membrane proteins included THY1 (GH), ADD1 and TSPAN6 (PRL), and CX3CR1, FOLR1, and RAMP1 (NFPA). Docking analysis highlighted strong binding affinities between several natural compounds and proteins FOLR1, GRIK1, and TLN1. The FDA-approved drug Mirvetuximab soravtansine also showed potential in targeting FOLR1. Conclusion Subtype-specific and shared membrane proteins in PAs represent viable diagnostic and therapeutic targets. Natural compounds and repurposed drugs may offer new treatment strategies, particularly for non-functional and invasive PAs. Pituitary adenoma Gene expression Diagnostic-therapeutic biomarkers plant-derived compounds small molecules therapeutic strategies Figures Figure 1 Figure 2 Figure 3 1. Introduction Pituitary adenomas (PAs) are endocrine neoplasms that arise from the anterior pituitary gland and constitute approximately 10–15% of all intracranial tumors [ 1 , 2 ]. While most are histologically benign, they can cause significant morbidity due to hormonal imbalances or mass effects. Around one-third of PAs are considered non-functional pituitary adenomas (NFPAs), which do not secrete active hormones. These tumors often present late and are more difficult to manage, especially when invasive [ 3 ]. Current treatment strategies include surgery, radiotherapy, and limited pharmacologic interventions. Functional PAs can often be treated with somatostatin analogs or dopamine receptor agonists, whereas effective pharmacological treatments for NFPAs remain scarce. Additionally, some pituitary tumors exhibit resistance or recurrence, highlighting the need for more targeted and durable therapies. Precision medicine offers a potential path forward, particularly through the identification of molecular markers specific to tumor subtypes. For pituitary adenomas (PAs), progressing beyond histological classification towards molecular profiling has recently led to the identification of distinct transcriptomic subtypes with prognostic and therapeutic relevance [ 4 , 5 ]. Membrane proteins are especially appealing due to their extracellular localization, which makes them accessible for therapeutic targeting and imaging. While deregulated expression of membrane proteins has been documented in several cancers, such as breast and colorectal tumors, detailed and subtype-resolved analyses in PAs remain scarce [ 6 ]. Recent advances in transcriptomic and computational biology have made it feasible to perform large-scale comparative analyses and integrate these findings with drug discovery efforts. Such multidimensional data integration is pivotal for identifying membrane protein targets that may also serve as biomarkers or therapeutic entry points [ 7 ]. Natural compounds have shown anti-tumor activity in several in vitro and in vivo models of PA. For instance, curcumin demonstrated not only growth inhibition of GH3 rat pituitary tumor cells in vitro but also reduced tumor burden in nude mice, mediated via mitochondrial dysfunction and NF-κB pathway suppression [ 8 ]. Similarly, other phytochemicals like 18β‑glycyrrhetinic acid, matrine, and grifolic acid have illustrated cytotoxic effects through MAPK and AKT pathway modulation. Tetrandrine has also been shown to induce autophagy and apoptosis in PA cells via MAPK/STAT3 attenuation in vitro and in vivo [ 9 ]. In this study, we conducted an integrative bioinformatics analysis using public transcriptomic datasets to identify differentially expressed membrane proteins in major PA subtypes compared to normal pituitary tissue. We then performed molecular docking to assess the potential of plant-derived compounds and known small molecules to target these proteins, aiming to prioritize candidates for experimental validation and drug development. 2. Method 2.1. Data collection and preprocessing We searched the Gene Expression Omnibus (GEO) database for microarray datasets of human pituitary adenomas and normal pituitary tissue. Eight datasets were selected based on criteria including sample size, annotation quality, and inclusion of major PA subtypes (Table 1 ). The final cohort comprised 77 tumor and 25 normal samples, covering GH, ACTH, PRL-secreting adenomas, NFPAs, and null cell adenomas. Data preprocessing involved background correction, normalization, and summarization using the Robust Multi-array Averaging (RMA) algorithm in the Limma package (R version 4.2.0). Batch effects from different platforms were corrected using the ComBat function from the SVA package. Only genes common to all datasets (7859 symbols) were used for downstream analyses. 2.2. Differential expression analysis For each PA subtype, differential gene expression was analyzed by comparing tumor samples with normal pituitary samples. The Limma package was used to compute log2 fold changes (logFC) and adjusted p-values. A threshold of adjusted p ≤ 0.05 and |logFC| ≥ 1.0 (2-fold change) was used to define significant DEGs. In subtypes with few DEGs, a more lenient cutoff of |logFC| ≥ 0.58 (1.5-fold change) was applied. Then we compared the lists of up-and down-regulated genes among all 5 comparisons (ACTH, GH, PRL, NFPA, and NULL compared with normal tissues) to find shared deregulated genes between two or more PA subtypes as well as the specific deregulated genes in each subtype. 2.3. Gene and pathway enrichment analysis To find the corresponding functions and associated pathways of the identified deregulated genes, we performed gene and pathway enrichment analysis using the ‘EnrichR’ web server. 2.4. Drug Repositioning and Compound Availability We explored chemical databases (e.g., PubChem, Tocris, Sigma-Aldrich) to identify approved or experimental drugs matching our target proteins. The FDA-approved drug Mirvetuximab soravtansine, which targets FOLR1, was selected for additional docking simulations. 2.5. Molecular Docking Workflow Target protein structures were obtained from the Protein Data Bank (PDB) and AlphaFold databases. Protein preparation involved removing non-relevant chains and optimizing structures using UCSF Chimera. A library of 490 plant-derived anticancer compounds and relevant small molecules was curated from literature and public databases. Molecular docking was performed using PyRx with the AutoDock Vina engine. Binding affinity was calculated for each ligand-protein pair. The top 10 ligands for each protein based on binding energy were retained for further analysis. 3. Results Table 2 presents the number of deregulated genes in each pituitary adenoma (PA) subtype, including those shared with one or more subtypes. Subtype-specific deregulated genes are indicated in parentheses. A comprehensive list of deregulated genes identified in each subtype, compared to normal pituitary tissue, is provided in Supplementary Table 1. To explore the biological functions of these genes, we performed KEGG pathway enrichment analysis. Based on established criteria from previous studies regarding suitable candidates for targeted diagnosis or therapy, our analysis primarily focused on upregulated cell membrane genes in PAs. 3.1. Shared targets across all PA subtypes A total of 25 deregulated genes were found to be shared across all PA subtypes when compared to normal pituitary tissue, including two upregulated and 23 downregulated genes (Supplementary Table 1). Among these, two were identified as cell membrane proteins: FILIP1L (upregulated) and ISRL (downregulated) (Table 3 ). 3.2. Type-Specific gene expression in PAs The analysis revealed several subtype-specific gene expression changes in pituitary adenomas (PAs) compared to normal pituitary tissue. Notably, six upregulated membrane proteins were identified by comparing gene expression profiles between invasive and non-invasive non-functional PAs (NFPAs). Figure 1 illustrates the cell membrane protein genes with subtype-specific expression alterations (both upregulated and downregulated) across PA subtypes. As the primary goal of this study was to identify potential drug targets for different PA subtypes, we focused on upregulated genes. These are presented and discussed in detail. The molecular functions of the upregulated, subtype-specific membrane protein targets are summarized in Table 4 . Pathway enrichment analysis of these subtype-specific upregulated genes revealed a limited number of enriched pathways in invasive NFPA, non-invasive NFPA, general NFPA, and GH-producing adenomas (Fig. 2 ). 3.3. Docking of Plant-Derived Compounds The three-dimensional structures of the target proteins—FOLR1, GRIK1, and TLN1—were retrieved from the Protein Data Bank (PDB), with corresponding identifiers listed in Supplementary Table 2. These structures were pre-processed for molecular docking by removing non-essential chains unrelated to the active sites using UCSF Chimera, followed by energy minimization to enhance structural stability. A library of 490 plant-derived compounds with reported anticancer activity was compiled from peer-reviewed literature. Additionally, small molecules with known inhibitory effects on the target proteins were collected from relevant databases and publications. Molecular docking was performed using PyRx software, employing the AutoDock Vina algorithm to evaluate the binding affinity of each compound to the target proteins. For each protein, the top 10 plant-derived compounds showing the strongest binding affinities (measured in kcal/mol) were selected. The docking results for each protein are presented in Table 5 . 3.4. Docking of Small Molecules To evaluate the availability of small-molecule inhibitors, a comprehensive search was conducted across major chemical databases and research chemical suppliers, including Tocris Bioscience, Hello Bio, Sigma-Aldrich, Enzo Life Sciences, and STEMCELL Technologies (Table 6 and Supplementary Table 3). The search identified several commercially available compounds suitable for research use, including LY466195, UBP302, UBP310, ACET, CNQX, DNQX, and NBQX. 3.5. Docking of Identified Drugs Mirvetuximab soravtansine (PubChem ID: 91810695) is an FDA-approved antibody-drug conjugate, authorized in November 2022 for the treatment of ovarian cancer with high FOLR1 expression. It specifically binds to FOLR1, making it a potential candidate for repurposing in pituitary adenomas. Docking analysis demonstrated a favorable binding affinity with FOLR1 (− 8.4 kcal/mol). No FDA-approved drugs were identified for the other target proteins, GRIK1 and TLN1. 4. Discussion Ideal tumor targets are characterized by membrane localization, exclusive upregulation in tumor versus normal cells, high protein abundance per cell, and widespread expression within the tumor. Thus, membrane protein overexpression in tumors highlights them as strong candidates for targeted imaging or drug delivery[ 10 ]. To pinpoint deregulated membrane proteins in each PA subtype, we analyzed eight gene expression datasets. Our findings revealed distinct transcriptional signatures per subtype, with NFPAs showing the highest number of subtype-specific deregulations, especially in membrane proteins—the primary focus of this discussion. 4.1. GH secreting adenoma The overexpression of THY1 in PA stem-like cells (PASC) has previously been indicated [ 11 ]. In addition, Thy1 expressing cells indicate invasive and metastatic properties in several cancers [ 12 – 15 ]. CHRNA3 is a ligand-gated ion channel and its correlation with cancer development in cigarette smokers has been demonstrated. CHRNA3 is a part of the carcinogenesis-receptor activation pathway that upon binding to nicotine activates the PI3K-Akt pathway resulting in the proliferation and apoptotic inhibition in lung cancer [ 16 ]. 4.2. Prolactinoma ADD1 (Adducin), involved in membrane cytoskeleton stabilization, has shown dual roles in cancer. Its downregulation in ovarian cancer and glioblastoma suggests a tumor suppressor function, while its overexpression in lung, murine breast, and colorectal cancers indicates oncogenic potential [ 17 ]. TSPAN6 (Tetraspanin-6), a member of the transmembrane 4 superfamily and regulator of synaptic transmission, is overexpressed in the prefrontal cortex of Alzheimer’s patients and linked to disease progression [ 18 ]. Tetraspanins, including TSPAN6, are also implicated in cancer invasion and metastasis via cancer–endothelial cell interactions [ 19 ]. 4.3. NFPA NFPAs exhibited the highest number of subtype-specific differentially expressed genes (DEGs) among pituitary adenomas, aligning with previous findings by Chen et al. [ 20 ]. One notable upregulated gene was CD200, an immunosuppressive molecule associated with poor prognosis in multiple cancers such as multiple myeloma, AML, CLL, and rectal cancer. CD200-expressing tumor cells have been shown to suppress T-cell responses, contributing to immune evasion[ 21 ]. CX3CR1, involved in the chemokine signaling pathway, was also upregulated and may play a role in pituitary vascular remodeling by facilitating differentiation of progenitor cells into endothelial cells [ 22 ]. This receptor, predominantly expressed in microglia, interacts with neuronal CX3CL1 to regulate CNS homeostasis and inflammatory responses. Disruption of the CX3CL1–CX3CR1 axis, similar to the CD200–CD200R pathway, has been linked to neuro-inflammation and neurodegeneration [ 23 ]. The CACNA2D1 gene, associated with MAPK and oxytocin signaling, was significantly upregulated in invasive NFPAs. Its expression is regulated by hyper-methylation of hsa-miR-150-5p, and it has been implicated in therapy resistance in cancer stem-like cells in NSCLC [ 24 , 25 ]. Another upregulated gene, ATP2B1, is crucial for calcium export from the cytoplasm, and its dysregulation may contribute to neurodegenerative diseases such as AD, PD, and ALS. Its expression was also elevated in fish hypothalamus exposed to the pesticide Dieldrin, raising environmental health concerns [ 26 , 27 ]. SDC4 (Syndecan-4), a cell surface proteoglycan, regulates actin cytoskeleton and mechanotransduction signaling in folliculostellate (FS) cells of the anterior pituitary, which function in hormone regulation and stem-like activity. Its role in PKCα-mediated signaling underscores its importance in tumor cell contractility and migration [ 28 , 29 ]. FOLR1, another significantly overexpressed gene in NFPAs (but downregulated in GH-secreting adenomas), enhances folate uptake and may promote tumor proliferation. Due to its selective expression in several epithelial tumors, FOLR1 is being actively explored in clinical trials as a diagnostic and therapeutic target using antibody- and folic acid–based delivery system[ 30 – 32 ]. RAMP1, known to regulate angiogenesis, was also upregulated. Its inhibition has been shown to suppress vascular formation in endometriosis and brain endothelial cells, suggesting a potential role in NFPA angiogenic remodeling [ 33 , 34 ]. Other upregulated genes included SEMA4F, a semaphorin involved in cell guidance. Though some studies suggest its tumor-suppressive role in cancers like neurofibroma and breast cancer, others highlight oncogenic potential in prostate cancer [ 35 – 37 ]. EFNB3, a ligand for Eph receptors, is involved in cellular adhesion and migration and is associated with favorable prognosis in neuroblastoma [ 38 – 40 ]. Interestingly, ADAM23, typically a tumor suppressor with an inactive metalloprotease domain, was found upregulated. This unexpected result may reflect intratumoral heterogeneity or sample limitations, and further studies are needed to clarify its role in NFPAs [ 41 , 42 ]. TSPAN1, promoting migration and survival in prostate cancer, and CHRNA5, linked to addiction and cancer susceptibility, were also NFPA-specific upregulated genes [ 43 – 45 ]. Lastly, NRXN1, essential for exocytosis in the pituitary gland, was overexpressed. Along with its ligand NXPH1, it is associated with cancer stemness and chemoresistance in neuroblastoma [ 46 ]. 4.4. Invasive NFPA Several genes were specifically upregulated in invasive NFPAs. GRIK1, a glutamate receptor involved in synaptic plasticity and neuronal signaling, was overexpressed. Its elevated expression has been linked to cognitive impairment in Down syndrome, a feature also observed in pituitary adenomas [ 34 ][ 45 ]. Similarly, GRIA3, another glutamate receptor, was found upregulated. It has been identified as a potential therapeutic target in TSH-secreting adenomas and is implicated in reduced apoptosis and increased proliferation in pancreatic cancer [ 47 , 48 ]. ATP2B2, like ATP2B1, encodes a Ca²⁺-ATPase and is involved in cAMP, calcium, and cGMP-PKG signaling pathways. Dysregulation of intracellular calcium levels may contribute to neurodegeneration. MMP16, another upregulated gene, is a matrix metalloproteinase regulated by the tumor-suppressor miR-146a. Its induction plays a role in Wnt-mediated cancer progression and metastasis in gastric cancer and promotes tumor invasion and lymphatic spread in melanoma by disrupting cell adhesion and collagen alignment [ 49 , 50 ]. 4.5. Non-Invasive NFPA TLN1 was the only upregulated cell membrane gene in non-invasive NFPA, involved in the actin cytoskeleton and tumor cell migration via the Rap1 signaling pathway (Fig. 2 C). A recent proteomic study found TLN1 downregulated in fibroblasts from invasive NFPA with bone destruction, suggesting a potential role in distinguishing invasive from non-invasive subtypes [ 51 ]. Given that effective targeted therapy relies on high or selective expression of surface proteins in tumors, the overexpressed cell membrane proteins identified here may serve as ideal candidates for monoclonal antibody-based strategies. These include nano-drug delivery systems, CAR-T therapies, and radioisotope-based diagnostics or treatments tailored to PA subtypes (Fig. 3 ). 4.6. Potential treatments NFPAs account for roughly one-third of all pituitary tumors. While typically benign, their progression to malignancy remains poorly understood and may involve genetic and epigenetic alterations. Pituitary carcinomas are extremely rare, representing only 0.1–0.5% of cases. Current NFPA treatments include surgery, radiotherapy, medical therapy, or active monitoring. However, complete resection of large macroadenomas is often challenging, and recurrence rates remain high [ 52 ]. Thus, there is growing interest in novel, targeted therapies—particularly from natural sources—due to their efficacy and lower toxicity. Plant-derived compounds and small molecules have shown promise in preclinical studies by modulating molecular pathways involved in tumor growth and hormone regulation. For instance, SZ-685C, a marine anthraquinone from Halorosellinia sp., induces apoptosis in primary human NFPA cells via Akt pathway inhibition [ 53 ]. Additionally, shared overexpressed membrane proteins may serve as differential markers between normal and adenoma cells and offer targets for broad-spectrum therapies. Molecular docking results suggest several plant-based compounds and small molecules may inhibit key NFPA proteins such as FOLR1, GRIK1, and TLN1, supporting their potential as therapeutic leads (Tables 5 – 6 ). Furthermore, drug repositioning—repurposing existing drugs for new indications—may offer viable strategies. For example, the anti-breast cancer agent Mirvetuximab soravtansine, which targets FOLR1, could potentially be repurposed for NFPA treatment [ 54 ]. 5. Conclusion Distinct groups of cell membrane proteins are potential targets for tumor detection or targeted drug delivery to tumor cells. However, treatment of solid tumors is challenging, especially for those with very high tumor heterogeneity. Therefore, targeting specific cell membrane proteins could improve pharmaceutical treatments of these tumors. Further clinical research is necessary to validate these findings and translate them into effective treatments for patients with pituitary adenomas. Declarations Acknowledgment This study was supported by the Iran University of Medical Sciences (Grant No. IR.IUMS.REC.1398.632). The authors gratefully acknowledge this support. Funding Grant No. IR.IUMS.REC.1398.632 Conflict of interest The authors declare that they have no conflicts of interest. Ethical Approval IR.IUMS.REC.1398.632 Authors Contributions M.H designed the work. N.H and YB performed bioinformatics analyses. MH and N.H, interpreted the result. N.H wrote the manuscript. M.H and N.H revised the final version of manuscript. Data availability Publicly available datasets were analyzed in this study. The data are openly available in NCBI (GEO DataSets). References Imani, M., et al., Comparison of cabergoline versus raloxifene add-on therapy to long-acting somatostatin analogue in patients with inadequately controlled acromegaly: A randomized open label clinical trial. Endocrine Practice, 2018. 24 (6): p. 542-547. Miermeister, C.P., et al., Histological criteria for atypical pituitary adenomas–data from the German pituitary adenoma registry suggests modifications. Acta neuropathologica communications, 2015. 3 (1): p. 1-11. Ghadir, M., et al., Cell proliferation, apoptosis, and angiogenesis in non-functional pituitary adenoma: association with tumor invasiveness. Endocrine, 2020. 69 (3): p. 596-603. Aboregela, A.M., Approaches based on natural products and miRNAs in pituitary adenomas: unveiling therapeutic intervention. Naunyn-Schmiedeberg's Archives of Pharmacology, 2025. 398 (1): p. 69-88. Peng, J., et al., Comprehensive transcriptomic analysis identifies three distinct subtypes of pituitary adenomas: insights into tumor behavior, prognosis, and stem cell characteristics. Journal of Translational Medicine, 2024. 22 (1): p. 892. Grimm, D., et al., Diagnostic and therapeutic use of membrane proteins in cancer cells. Current medicinal chemistry, 2011. 18 (2): p. 176-190. He, B., et al., ASGARD is a single-cell guided pipeline to aid repurposing of drugs. Nature Communications, 2023. 14 (1): p. 993. Wu, H., et al., Genetic and Functional Changes in Mitochondria in the Pituitary Adenoma: The Pathogenesis and Its Therapy. Antioxidants, 2024. 13 (12): p. 1514. Lyu, L., et al., Autophagy inhibition enhances anti‐pituitary adenoma effect of tetrandrine. Phytotherapy Research, 2021. 35 (7): p. 4007-4021. Boonstra, M.C., et al., Selecting targets for tumor imaging: an overview of cancer-associated membrane proteins. Biomarkers in cancer, 2016. 8 : p. BIC. S38542. Xu, Q., et al., Isolation of tumour stem-like cells from benign tumours. British journal of cancer, 2009. 101 (2): p. 303-311. Zhu, L., et al., Evidence of CD90+ CXCR4+ cells as circulating tumor stem cells in hepatocellular carcinoma. Tumor Biology, 2015. 36 (7): p. 5353-5360. Yamashita, T., et al., Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma. Hepatology, 2013. 57 (4): p. 1484-1497. Ohga, N., et al., Heterogeneity of tumor endothelial cells: comparison between tumor endothelial cells isolated from high-and low-metastatic tumors. The American journal of pathology, 2012. 180 (3): p. 1294-1307. Avril, T., E. Vauleon, and E. Chevet, Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. Oncogenesis, 2017. 6 (8): p. e373-e373. Zhao, Y., The oncogenic functions of nicotinic acetylcholine receptors. Journal of oncology, 2016. 2016 . Luo, C. and J. Shen, Adducin in tumorigenesis and metastasis. Oncotarget, 2017. 8 (29): p. 48453. Perot, B.P. and M.M. Ménager, Tetraspanin 7 and its closest paralog tetraspanin 6: membrane organizers with key functions in brain development, viral infection, innate immunity, diabetes and cancer. Medical Microbiology and Immunology, 2020. 209 : p. 427-436. Detchokul, S., et al., Tetraspanins as regulators of the tumour microenvironment: implications for metastasis and therapeutic strategies. British journal of pharmacology, 2014. 171 (24): p. 5462-5490. Chen, Y., et al., Genomic and transcriptomic analysis of pituitary adenomas reveals the impacts of copy number variations on gene expression and clinical prognosis among prolactin-secreting subtype. Aging (Albany NY), 2021. 13 (1): p. 1276. Bisgin, A., et al., Interaction of CD200 overexpression on tumor cells with CD200R1 overexpression on stromal cells: an escape from the host immune response in rectal cancer patients. Journal of oncology, 2019. 2019 . Horiguchi, K., et al., CX3CL1/CX3CR1-signalling in the CD9/S100β/SOX2-positive adult pituitary stem/progenitor cells modulates differentiation into endothelial cells. Histochemistry and cell biology, 2020. 153 (6): p. 385-396. Chamera, K., et al., The prenatal challenge with lipopolysaccharide and polyinosinic: polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: A link to schizophrenia-like behaviours. Journal of neuroinflammation, 2020. 17 (1): p. 1-24. Boresowicz, J., et al., DNA methylation influences mirna expression in gonadotroph pituitary tumors. Life, 2020. 10 (5): p. 59. Sui, X., et al., Calcium channel α2δ1 subunit (CACNA2D1) enhances radioresistance in cancer stem-like cells in non-small cell lung cancer cell lines. Cancer management and research, 2018. 10 : p. 5009. Hwang, S.-M., et al., The role of TRP channels and PMCA in brain disorders: intracellular calcium and pH homeostasis. Frontiers in Cell and Developmental Biology, 2021. 9 : p. 57. Martyniuk, C.J., et al., Genomic and proteomic responses to environmentally relevant exposures to dieldrin: indicators of neurodegeneration? Toxicological Sciences, 2010. 117 (1): p. 190-199. Horiguchi, K., et al., Expression of the proteoglycan syndecan-4 and the mechanism by which it mediates stress fiber formation in folliculostellate cells in the rat anterior pituitary gland. Journal of endocrinology, 2012. 214 (2): p. 199. Huang, C.-P., et al., Syndecan-4 promotes epithelial tumor cells spreading and regulates the turnover of PKCα Activity under mechanical stimulation on the elastomeric substrates. Cellular Physiology and Biochemistry, 2015. 36 (4): p. 1291-1304. Necela, B.M., et al., Folate receptor-α (FOLR1) expression and function in triple negative tumors. PloS one, 2015. 10 (3): p. e0122209. Evans, C.O., et al., Folate receptor expression in pituitary adenomas: cellular and molecular analysis. Vitamins & Hormones, 2008. 79 : p. 235-266. Larysz, D., et al., Expression of genes FOLR1, BAG1 and LAPTM4B in functioning and non-functioning pituitary adenomas. Folia neuropathologica, 2012. 50 (3): p. 277-286. Honda, M., et al., Inhibition of receptor activity–modifying protein 1 suppresses the development of endometriosis and the formation of blood and lymphatic vessels. Journal of cellular and molecular medicine, 2020. 24 (20): p. 11984-11997. Zhang, Q., et al., The influence of receptor activity–modifying protein‐1 overexpression on angiogenesis in mouse brain capillary endothelial cells. Journal of cellular biochemistry, 2019. 120 (6): p. 10087-10096. Carulli, D., F. De Winter, and J. Verhaagen, Semaphorins in Adult Nervous System Plasticity and Disease. Frontiers in synaptic neuroscience, 2021. 13 : p. 20. Neufeld, G., et al., The role of the semaphorins in cancer. Cell Adhesion & Migration, 2016. 10 (6): p. 652-674. Ding, Y., et al., Semaphorin 4F as a critical regulator of neuroepithelial interactions and a biomarker of aggressive prostate cancer. Clinical Cancer Research, 2013. 19 (22): p. 6101-6111. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Research, 2021. 49 (D1): p. D480-D489. Tang, X.X., et al., High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas. Clinical Cancer Research, 1999. 5 (6): p. 1491-1496. Tang, X.X., et al., Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma. Proceedings of the National Academy of Sciences, 2000. 97 (20): p. 10936-10941. Hu, C., et al., The expression of ADAM23 and its correlation with promoter methylation in non‐small‐cell lung carcinoma. International journal of experimental pathology, 2011. 92 (5): p. 333-339. Costa, E., et al., Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals. Oncogene, 2015. 34 (10): p. 1270-1279. Munkley, J., et al., The cancer-associated cell migration protein TSPAN1 is under control of androgens and its upregulation increases prostate cancer cell migration. Scientific reports, 2017. 7 (1): p. 1-11. Zemkova, H., et al., Multiple cholinergic signaling pathways in pituitary gonadotrophs. Endocrinology, 2013. 154 (1): p. 421-433. Smith, R.M., et al., Nicotinic α 5 receptor subunit mRNA expression is associated with distant 5′ upstream polymorphisms. European Journal of Human Genetics, 2011. 19 (1): p. 76-83. Fanlo Escudero, L., Neuroblastoma cancer stem cells: The role of NXPH1 and its receptor α-NRXN1. 2019. Taniguchi-Ponciano, K., et al., Transcriptome and methylome analysis reveals three cellular origins of pituitary tumors. Scientific reports, 2020. 10 (1): p. 1-11. Ripka, S., et al., Glutamate receptor GRIA3—target of CUX1 and mediator of tumor progression in pancreatic cancer. Neoplasia, 2010. 12 (8): p. 659-IN6. Zhang, C., et al., MicroRNAs Regulated Brain Tumor Cell Phenotype and Their Therapeutic Potential . 2013: IntechOpen. Tatti, O., et al., MMP16 mediates a proteolytic switch to promote cell–cell adhesion, collagen alignment, and lymphatic invasion in melanoma. Cancer research, 2015. 75 (10): p. 2083-2094. Zhang, L.-y., et al., Fibroblasts play a potential role in bone destruction via osteopontin related caldesmon expression and polymerization in human non-functioning pituitary adenomas. Scientific reports, 2017. 7 (1): p. 1-10. Vargas-Ortega, G., B. Gonzalez-Virla, and C.A. Romero-Gameros, Pharmacological treatment of non-functioning pituitary adenomas. Archives of Medical Research, 2023. 54 (8): p. 102917. Wang, X., et al., The marine metabolite SZ-685C induces apoptosis in primary human nonfunctioning pituitary adenoma cells by inhibition of the Akt pathway in vitro. Marine drugs, 2015. 13 (3): p. 1569-1580. Zamami, Y., et al., Drug-repositioning approaches based on medical and life science databases. Frontiers in Pharmacology, 2021. 12 : p. 752174. Tables Table 1: Series IDs, number of samples, subtypes of PAs, and microarray platform of datasets. Series ID Number of samples PA subtypes Platform GSE119063 9 5 PRL, 4 normal human pituitaries Agilent GSE93825 40 40 ACTH secreting PA Illumina Human HT-12 WG-DASL V4.0 R2 expression bead chip GSE63357 25 13 GH secreting PA, 7 non-functioning PA, 5 normal human pituitary Affymetrix GSE51618 10 4 non-Invasive non-functioning PA, 3 Invasive non-functioning PA, 3 normal human pituitary Agilent GSE36314 7 4 PRL, 3 normal human pituitary Affymetrix GSE26966 23 14 Null, 9 normal human pituitary Affymetrix GSE2175 5 1 non-functioning PA, 1 ACTH secreting PA, 1 GH secreting PA, 1 PRL, 1 normal human pituitary Affymetrix GSE22812 13 6 Aggressive-Invasive, 2 Invasive, and 5 non-Invasive PRL GE Healthcare/Amersham BiosciencesCodelink Human whole Genome Bioarray Table 2: Comparison of groups and the number of shared deregulated genes with one or more subtypes. The number of exclusively deregulated genes in each comparison group is shown in parentheses. “no” indicates that no exclusive deregulated genes were identified in that group.. Comparing groups # Down-regulated genes # Up-regulated genes ACTH Vs. normal 97(no) 64(1) GH Vs. normal 151(8) 89(62) Invasive NFPA Vs. Non-invasive NFPA 2(2) 2(2) Invasive NFPA Vs. normal 129(22) 51(21) NFPA Vs. normal 377(74) 348(185) Non-Invasive Vs. normal 194(13) 99(5) Null Vs. normal 359(27) 120(1) PRL Vs. normal 240(9) 27(no) Merged NFPA (with NFPA, Invasive NFPA, and non-invasive NFPA labels) Vs. normal 299(1) 167(no) Table 3: Shared DEGs among all types of PA. Symbol Gene name Function Adenoma type (log 2 FC) FILIP1l (up) FilaminA Interacting Protein 1 Like Regulator of the antiangiogenic activity, Leads to inhibition of cell proliferation and migration and an increase in apoptosis GH (0.76), PRL (1.06), ACTH (1.07), NFPA (1.17), NULL (1.2) ISRL (down) Immunoglobulin Superfamily Containing Leucine Rich Repeat Mainly localized to the plasma membrane GH (-1.6), PRL (-1.8), ACTH ( -1.2), NFPA (-1.73), NULL ( -1.9) Table 4: Gene ontology of up-regulated PA type-specific targets. Adenoma type Type specific up-regulated cell membrane proteins Function GH THY1 Cell adhesion and cell communication CHRNA3 Ligand-gated ion channel, neurotransmission IGSF6 Transmembrane signaling receptor activity SLC26A4 Chloride transmembrane transporter activity NFPA CX3CR1 Adhesion and migration of leukocytes CNIH3 Regulating trafficking and gating properties of glutamate receptors, opioid dependence, voltage-gated calcium channel activity CD200 Have a role in immunosuppression and regulation of anti-tumor activity FOLR1 Transports 5-methyltetrahydrofolate into cells RAMP1 Required to transport calcitonin-receptor-like receptor to the plasma membrane, terminal glycosylation, maturation, and presentation of the CGRP receptor to the cell surface, neural development ATP2B1 Intracellular calcium homeostasis, cAMP signaling, and cGMP-PKG signaling pathways EFNB3 Ligand for Eph receptors, crucial for migration, repulsion, and adhesion during neuronal, vascular, and epithelial development ADAM23 Cell-cell and cell-matrix interactions, involved in fertilization, muscle development, and neurogenesis TSPAN1 signal transduction, cell development, activation, growth, and motility CHRNA5 Member of a superfamily of ligand-gated ion channels mediating fast signal transmission at synapses SDC4 Belongs to Heparan sulfate proteoglycans family NRXN1 Required for efficient neurotransmission, involved in the formation of synaptic contacts, cell-cell-interactions, exocytosis of secretory granules, and the regulation of signal transmission Invasive NFPA GRIK1 Predominant excitatory neurotransmitter receptors in the mammalian brain, involved in the normal neurophysiologic process GRIA3 Predominant excitatory neurotransmitter receptors in the mammalian brain, involved in the normal neurophysiologic process ATP2B2 Plays a critical role in intracellular calcium homeostasis MMP16 Involved in the breakdown of extracellular matrix in embryonic development, reproduction, and tissue remodeling, cancer development, progression, and metastasis Non-invasive NFPA TLN1 Involved in the attachment of adherent cells to extracellular matrices and of lymphocytes to other cells Table 5: Binding Affinity of Plant-Derived Compounds with FOLR1, GRIK1 and TLN1. Binding Affinity (kcal/mol) Compound name Ligand (PubChem ID) FOLR1 -11.9 Synthetic 53522790 -11.1 Synthetic 11936 -11.1 Synthetic 91742606 -11 Synthetic 101609000 -11 4-o-caffeoylshikimic acid 49821869 -10.9 FLAVONE 10680 -10.9 Synthetic 69531189 -10.9 Synthetic 91744068 -10.9 Geranial oxypeucedaninyl acetal 91750110 -10.7 Synthetic 101608999 GRIK1 -10.7 DESGLUCORUSCIN 90471987 -10.1 Luteolin 7-rutinoside 44258082 -9.9 Synthetic 53788517 -9.8 LMPK12111861 44258931 -9.6 Synthetic 101693312 -9.5 Hesperidin 10621 -9.5 Cannabisin-D 71448965 -9.4 Synthetic 102444811 -9.4 Synthetic 90473944 -9.4 malvidin 3-O-rutinoside 90657906 TLN1 -8.9 Oleanolic Acid 10494 -8.9 Bicyclomahanimbicine 77994099 -8.8 Synthetic 101280261 -8.7 Synthetic 101608999 -8.6 Synthetic 53788517 -8.6 Synthetic 90473944 -8.5 Synthetic 101609000 -8.4 Murrayazolinine 101856126 -8.2 Mudanpioside H 71457654 -8.2 Cholane-5,20(22)-diene-3b-phenoxy 91742606 Table 6 : Binding Affinity of Small Molecules with FOLR1 and GRIK1 Binding Affinity Compound name Ligand (PubChem ID) FOLR1 -9.5 ONX0801 135487419 GRIK1 -8.8 LY466195 9935648 -8.6 ACET 16125102 -8.5 NBQX 3272524 -7.5 CNQX 3721046 -7.3 DNQX 3899541 -7.3 UBP302 6420161 -7.1 UBP310 6420160 Additional Declarations No competing interests reported. Supplementary Files Supplementarytable1.xlsx Supplementarytable2.xlsx Supplementarytable3.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7604876","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":517260983,"identity":"3730650b-340e-440d-b384-abe69ad616d6","order_by":0,"name":"Maryam Honardoost","email":"","orcid":"","institution":"Iran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Maryam","middleName":"","lastName":"Honardoost","suffix":""},{"id":517260984,"identity":"600a9f95-2814-46aa-9587-918f3097fe0a","order_by":1,"name":"Yousof Bavafa Shandiz","email":"","orcid":"","institution":"Naghshejahan Higher Education 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1","display":"","copyAsset":false,"role":"figure","size":285110,"visible":true,"origin":"","legend":"\u003cp\u003eDeregulated type-specific cell membrane proteins in various PA types with their corresponding expressional fold changes.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7604876/v1/5cb0e11835c2f0687aa16611.png"},{"id":92095872,"identity":"e85864b4-3499-4c5a-9732-3351240cb8e2","added_by":"auto","created_at":"2025-09-24 14:37:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":228983,"visible":true,"origin":"","legend":"\u003cp\u003ePathways associated with up-regulated cell membrane proteins in invasive NFPA (a), non-invasive NFPA (b), NFPA (c), and GH (d).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7604876/v1/3e50ec461081458a6e3ec6f5.png"},{"id":92094550,"identity":"c94e189f-fe8f-4803-a41b-ea76f51a5a71","added_by":"auto","created_at":"2025-09-24 14:21:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":369994,"visible":true,"origin":"","legend":"\u003cp\u003eTarget-oriented delivery strategies of diagnostic/therapeutic agent site.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7604876/v1/f0e98f9d962449829568d506.png"},{"id":102295500,"identity":"444c508c-a320-4036-b8a6-f02d9d728273","added_by":"auto","created_at":"2026-02-10 10:11:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2237190,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7604876/v1/5165ba74-8bdc-4f30-8c6d-06d89bbf0df2.pdf"},{"id":92094552,"identity":"92208caa-52c2-465f-a060-56c4193cf509","added_by":"auto","created_at":"2025-09-24 14:21:21","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":45194,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7604876/v1/91f679e7cd4fc8b11267c13b.xlsx"},{"id":92095677,"identity":"da7a0166-c0a1-479f-b83c-3124504dfec1","added_by":"auto","created_at":"2025-09-24 14:29:21","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":9624,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7604876/v1/9d1cc84b530caa1d15e839da.xlsx"},{"id":92096770,"identity":"6154e1ee-84fe-447a-aa0e-9893c5758ef8","added_by":"auto","created_at":"2025-09-24 14:45:21","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":10436,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7604876/v1/862778b5126c45c9b1fb1c87.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Transcriptomic landscape of Pituitary Adenomas: potential diagnostic and therapeutic targets","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePituitary adenomas (PAs) are endocrine neoplasms that arise from the anterior pituitary gland and constitute approximately 10\u0026ndash;15% of all intracranial tumors [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While most are histologically benign, they can cause significant morbidity due to hormonal imbalances or mass effects. Around one-third of PAs are considered non-functional pituitary adenomas (NFPAs), which do not secrete active hormones. These tumors often present late and are more difficult to manage, especially when invasive [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCurrent treatment strategies include surgery, radiotherapy, and limited pharmacologic interventions. Functional PAs can often be treated with somatostatin analogs or dopamine receptor agonists, whereas effective pharmacological treatments for NFPAs remain scarce. Additionally, some pituitary tumors exhibit resistance or recurrence, highlighting the need for more targeted and durable therapies.\u003c/p\u003e\u003cp\u003ePrecision medicine offers a potential path forward, particularly through the identification of molecular markers specific to tumor subtypes. For pituitary adenomas (PAs), progressing beyond histological classification towards molecular profiling has recently led to the identification of distinct transcriptomic subtypes with prognostic and therapeutic relevance [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMembrane proteins are especially appealing due to their extracellular localization, which makes them accessible for therapeutic targeting and imaging. While deregulated expression of membrane proteins has been documented in several cancers, such as breast and colorectal tumors, detailed and subtype-resolved analyses in PAs remain scarce [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecent advances in transcriptomic and computational biology have made it feasible to perform large-scale comparative analyses and integrate these findings with drug discovery efforts. Such multidimensional data integration is pivotal for identifying membrane protein targets that may also serve as biomarkers or therapeutic entry points [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNatural compounds have shown anti-tumor activity in several in vitro and in vivo models of PA. For instance, curcumin demonstrated not only growth inhibition of GH3 rat pituitary tumor cells in vitro but also reduced tumor burden in nude mice, mediated via mitochondrial dysfunction and NF-κB pathway suppression [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Similarly, other phytochemicals like 18β‑glycyrrhetinic acid, matrine, and grifolic acid have illustrated cytotoxic effects through MAPK and AKT pathway modulation. Tetrandrine has also been shown to induce autophagy and apoptosis in PA cells via MAPK/STAT3 attenuation in vitro and in vivo [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, we conducted an integrative bioinformatics analysis using public transcriptomic datasets to identify differentially expressed membrane proteins in major PA subtypes compared to normal pituitary tissue. We then performed molecular docking to assess the potential of plant-derived compounds and known small molecules to target these proteins, aiming to prioritize candidates for experimental validation and drug development.\u003c/p\u003e"},{"header":"2. Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Data collection and preprocessing\u003c/h2\u003e\u003cp\u003eWe searched the Gene Expression Omnibus (GEO) database for microarray datasets of human pituitary adenomas and normal pituitary tissue. Eight datasets were selected based on criteria including sample size, annotation quality, and inclusion of major PA subtypes (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The final cohort comprised 77 tumor and 25 normal samples, covering GH, ACTH, PRL-secreting adenomas, NFPAs, and null cell adenomas.\u003c/p\u003e\u003cp\u003eData preprocessing involved background correction, normalization, and summarization using the Robust Multi-array Averaging (RMA) algorithm in the Limma package (R version 4.2.0). Batch effects from different platforms were corrected using the ComBat function from the SVA package. Only genes common to all datasets (7859 symbols) were used for downstream analyses.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Differential expression analysis\u003c/h2\u003e\u003cp\u003eFor each PA subtype, differential gene expression was analyzed by comparing tumor samples with normal pituitary samples. The Limma package was used to compute log2 fold changes (logFC) and adjusted p-values. A threshold of adjusted p\u0026thinsp;\u0026le;\u0026thinsp;0.05 and |logFC| \u0026ge; 1.0 (2-fold change) was used to define significant DEGs. In subtypes with few DEGs, a more lenient cutoff of |logFC| \u0026ge; 0.58 (1.5-fold change) was applied. Then we compared the lists of up-and down-regulated genes among all 5 comparisons (ACTH, GH, PRL, NFPA, and NULL compared with normal tissues) to find shared deregulated genes between two or more PA subtypes as well as the specific deregulated genes in each subtype.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Gene and pathway enrichment analysis\u003c/h2\u003e\u003cp\u003eTo find the corresponding functions and associated pathways of the identified deregulated genes, we performed gene and pathway enrichment analysis using the \u003cem\u003e\u0026lsquo;EnrichR\u0026rsquo;\u003c/em\u003e web server.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Drug Repositioning and Compound Availability\u003c/h2\u003e\u003cp\u003eWe explored chemical databases (e.g., PubChem, Tocris, Sigma-Aldrich) to identify approved or experimental drugs matching our target proteins. The FDA-approved drug Mirvetuximab soravtansine, which targets FOLR1, was selected for additional docking simulations.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e\u003cb\u003e2.5. Molecular Docking Workflow\u003c/b\u003e\u003c/h2\u003e\u003cp\u003eTarget protein structures were obtained from the Protein Data Bank (PDB) and AlphaFold databases. Protein preparation involved removing non-relevant chains and optimizing structures using UCSF Chimera. A library of 490 plant-derived anticancer compounds and relevant small molecules was curated from literature and public databases.\u003c/p\u003e\u003cp\u003eMolecular docking was performed using PyRx with the AutoDock Vina engine. Binding affinity was calculated for each ligand-protein pair. The top 10 ligands for each protein based on binding energy were retained for further analysis.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eTable\u0026nbsp;2 presents the number of deregulated genes in each pituitary adenoma (PA) subtype, including those shared with one or more subtypes. Subtype-specific deregulated genes are indicated in parentheses. A comprehensive list of deregulated genes identified in each subtype, compared to normal pituitary tissue, is provided in Supplementary Table\u0026nbsp;1. To explore the biological functions of these genes, we performed KEGG pathway enrichment analysis. Based on established criteria from previous studies regarding suitable candidates for targeted diagnosis or therapy, our analysis primarily focused on upregulated cell membrane genes in PAs.\u003c/p\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1. Shared targets across all PA subtypes\u003c/h2\u003e\n \u003cp\u003eA total of 25 deregulated genes were found to be shared across all PA subtypes when compared to normal pituitary tissue, including two upregulated and 23 downregulated genes (Supplementary Table\u0026nbsp;1). Among these, two were identified as cell membrane proteins: FILIP1L (upregulated) and ISRL (downregulated) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2. Type-Specific gene expression in PAs\u003c/h2\u003e\n \u003cp\u003eThe analysis revealed several subtype-specific gene expression changes in pituitary adenomas (PAs) compared to normal pituitary tissue. Notably, six upregulated membrane proteins were identified by comparing gene expression profiles between invasive and non-invasive non-functional PAs (NFPAs). Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the cell membrane protein genes with subtype-specific expression alterations (both upregulated and downregulated) across PA subtypes.\u003c/p\u003e\n \u003cp\u003eAs the primary goal of this study was to identify potential drug targets for different PA subtypes, we focused on upregulated genes. These are presented and discussed in detail. The molecular functions of the upregulated, subtype-specific membrane protein targets are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003ePathway enrichment analysis of these subtype-specific upregulated genes revealed a limited number of enriched pathways in invasive NFPA, non-invasive NFPA, general NFPA, and GH-producing adenomas (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3. Docking of Plant-Derived Compounds\u003c/h2\u003e\n \u003cp\u003eThe three-dimensional structures of the target proteins\u0026mdash;FOLR1, GRIK1, and TLN1\u0026mdash;were retrieved from the Protein Data Bank (PDB), with corresponding identifiers listed in Supplementary Table\u0026nbsp;2. These structures were pre-processed for molecular docking by removing non-essential chains unrelated to the active sites using UCSF Chimera, followed by energy minimization to enhance structural stability.\u003c/p\u003e\n \u003cp\u003eA library of 490 plant-derived compounds with reported anticancer activity was compiled from peer-reviewed literature. Additionally, small molecules with known inhibitory effects on the target proteins were collected from relevant databases and publications. Molecular docking was performed using PyRx software, employing the AutoDock Vina algorithm to evaluate the binding affinity of each compound to the target proteins.\u003c/p\u003e\n \u003cp\u003eFor each protein, the top 10 plant-derived compounds showing the strongest binding affinities (measured in kcal/mol) were selected. The docking results for each protein are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4. Docking of Small Molecules\u003c/h2\u003e\n \u003cp\u003eTo evaluate the availability of small-molecule inhibitors, a comprehensive search was conducted across major chemical databases and research chemical suppliers, including Tocris Bioscience, Hello Bio, Sigma-Aldrich, Enzo Life Sciences, and STEMCELL Technologies (Table \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e and Supplementary Table 3). The search identified several commercially available compounds suitable for research use, including LY466195, UBP302, UBP310, ACET, CNQX, DNQX, and NBQX.\u0026nbsp;\u003c/p\u003e\n \u003ch2\u003e\u003cstrong\u003e3.5. Docking of Identified Drugs\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eMirvetuximab soravtansine (PubChem ID: 91810695) is an FDA-approved antibody-drug conjugate, authorized in November 2022 for the treatment of ovarian cancer with high FOLR1 expression. It specifically binds to FOLR1, making it a potential candidate for repurposing in pituitary adenomas. Docking analysis demonstrated a favorable binding affinity with FOLR1 (\u0026minus;\u0026thinsp;8.4 kcal/mol). No FDA-approved drugs were identified for the other target proteins, GRIK1 and TLN1.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIdeal tumor targets are characterized by membrane localization, exclusive upregulation in tumor versus normal cells, high protein abundance per cell, and widespread expression within the tumor. Thus, membrane protein overexpression in tumors highlights them as strong candidates for targeted imaging or drug delivery[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo pinpoint deregulated membrane proteins in each PA subtype, we analyzed eight gene expression datasets. Our findings revealed distinct transcriptional signatures per subtype, with NFPAs showing the highest number of subtype-specific deregulations, especially in membrane proteins\u0026mdash;the primary focus of this discussion.\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e4.1. GH secreting adenoma\u003c/h2\u003e\u003cp\u003eThe overexpression of THY1 in PA stem-like cells (PASC) has previously been indicated [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, Thy1 expressing cells indicate invasive and metastatic properties in several cancers [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. CHRNA3 is a ligand-gated ion channel and its correlation with cancer development in cigarette smokers has been demonstrated. CHRNA3 is a part of the carcinogenesis-receptor activation pathway that upon binding to nicotine activates the PI3K-Akt pathway resulting in the proliferation and apoptotic inhibition in lung cancer [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e4.2. Prolactinoma\u003c/h2\u003e\u003cp\u003eADD1 (Adducin), involved in membrane cytoskeleton stabilization, has shown dual roles in cancer. Its downregulation in ovarian cancer and glioblastoma suggests a tumor suppressor function, while its overexpression in lung, murine breast, and colorectal cancers indicates oncogenic potential [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. TSPAN6 (Tetraspanin-6), a member of the transmembrane 4 superfamily and regulator of synaptic transmission, is overexpressed in the prefrontal cortex of Alzheimer\u0026rsquo;s patients and linked to disease progression [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Tetraspanins, including TSPAN6, are also implicated in cancer invasion and metastasis via cancer\u0026ndash;endothelial cell interactions [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e4.3. NFPA\u003c/h2\u003e\u003cp\u003eNFPAs exhibited the highest number of subtype-specific differentially expressed genes (DEGs) among pituitary adenomas, aligning with previous findings by Chen et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. One notable upregulated gene was CD200, an immunosuppressive molecule associated with poor prognosis in multiple cancers such as multiple myeloma, AML, CLL, and rectal cancer. CD200-expressing tumor cells have been shown to suppress T-cell responses, contributing to immune evasion[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. CX3CR1, involved in the chemokine signaling pathway, was also upregulated and may play a role in pituitary vascular remodeling by facilitating differentiation of progenitor cells into endothelial cells [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This receptor, predominantly expressed in microglia, interacts with neuronal CX3CL1 to regulate CNS homeostasis and inflammatory responses. Disruption of the CX3CL1\u0026ndash;CX3CR1 axis, similar to the CD200\u0026ndash;CD200R pathway, has been linked to neuro-inflammation and neurodegeneration [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The CACNA2D1 gene, associated with MAPK and oxytocin signaling, was significantly upregulated in invasive NFPAs. Its expression is regulated by hyper-methylation of hsa-miR-150-5p, and it has been implicated in therapy resistance in cancer stem-like cells in NSCLC [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Another upregulated gene, ATP2B1, is crucial for calcium export from the cytoplasm, and its dysregulation may contribute to neurodegenerative diseases such as AD, PD, and ALS. Its expression was also elevated in fish hypothalamus exposed to the pesticide Dieldrin, raising environmental health concerns [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. SDC4 (Syndecan-4), a cell surface proteoglycan, regulates actin cytoskeleton and mechanotransduction signaling in folliculostellate (FS) cells of the anterior pituitary, which function in hormone regulation and stem-like activity. Its role in PKCα-mediated signaling underscores its importance in tumor cell contractility and migration [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFOLR1, another significantly overexpressed gene in NFPAs (but downregulated in GH-secreting adenomas), enhances folate uptake and may promote tumor proliferation. Due to its selective expression in several epithelial tumors, FOLR1 is being actively explored in clinical trials as a diagnostic and therapeutic target using antibody- and folic acid\u0026ndash;based delivery system[\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. RAMP1, known to regulate angiogenesis, was also upregulated. Its inhibition has been shown to suppress vascular formation in endometriosis and brain endothelial cells, suggesting a potential role in NFPA angiogenic remodeling [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Other upregulated genes included SEMA4F, a semaphorin involved in cell guidance. Though some studies suggest its tumor-suppressive role in cancers like neurofibroma and breast cancer, others highlight oncogenic potential in prostate cancer [\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. EFNB3, a ligand for Eph receptors, is involved in cellular adhesion and migration and is associated with favorable prognosis in neuroblastoma [\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eInterestingly, ADAM23, typically a tumor suppressor with an inactive metalloprotease domain, was found upregulated. This unexpected result may reflect intratumoral heterogeneity or sample limitations, and further studies are needed to clarify its role in NFPAs [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. TSPAN1, promoting migration and survival in prostate cancer, and CHRNA5, linked to addiction and cancer susceptibility, were also NFPA-specific upregulated genes [\u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Lastly, NRXN1, essential for exocytosis in the pituitary gland, was overexpressed. Along with its ligand NXPH1, it is associated with cancer stemness and chemoresistance in neuroblastoma [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e4.4. Invasive NFPA\u003c/h2\u003e\u003cp\u003eSeveral genes were specifically upregulated in invasive NFPAs. GRIK1, a glutamate receptor involved in synaptic plasticity and neuronal signaling, was overexpressed. Its elevated expression has been linked to cognitive impairment in Down syndrome, a feature also observed in pituitary adenomas [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e][\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Similarly, GRIA3, another glutamate receptor, was found upregulated. It has been identified as a potential therapeutic target in TSH-secreting adenomas and is implicated in reduced apoptosis and increased proliferation in pancreatic cancer [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eATP2B2, like ATP2B1, encodes a Ca\u0026sup2;⁺-ATPase and is involved in cAMP, calcium, and cGMP-PKG signaling pathways. Dysregulation of intracellular calcium levels may contribute to neurodegeneration. MMP16, another upregulated gene, is a matrix metalloproteinase regulated by the tumor-suppressor miR-146a. Its induction plays a role in Wnt-mediated cancer progression and metastasis in gastric cancer and promotes tumor invasion and lymphatic spread in melanoma by disrupting cell adhesion and collagen alignment [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e4.5. Non-Invasive NFPA\u003c/h2\u003e\u003cp\u003eTLN1 was the only upregulated cell membrane gene in non-invasive NFPA, involved in the actin cytoskeleton and tumor cell migration via the Rap1 signaling pathway (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). A recent proteomic study found TLN1 downregulated in fibroblasts from invasive NFPA with bone destruction, suggesting a potential role in distinguishing invasive from non-invasive subtypes [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eGiven that effective targeted therapy relies on high or selective expression of surface proteins in tumors, the overexpressed cell membrane proteins identified here may serve as ideal candidates for monoclonal antibody-based strategies. These include nano-drug delivery systems, CAR-T therapies, and radioisotope-based diagnostics or treatments tailored to PA subtypes (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e4.6. Potential treatments\u003c/h2\u003e\u003cp\u003eNFPAs account for roughly one-third of all pituitary tumors. While typically benign, their progression to malignancy remains poorly understood and may involve genetic and epigenetic alterations. Pituitary carcinomas are extremely rare, representing only 0.1\u0026ndash;0.5% of cases. Current NFPA treatments include surgery, radiotherapy, medical therapy, or active monitoring. However, complete resection of large macroadenomas is often challenging, and recurrence rates remain high [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Thus, there is growing interest in novel, targeted therapies\u0026mdash;particularly from natural sources\u0026mdash;due to their efficacy and lower toxicity.\u003c/p\u003e\u003cp\u003ePlant-derived compounds and small molecules have shown promise in preclinical studies by modulating molecular pathways involved in tumor growth and hormone regulation. For instance, SZ-685C, a marine anthraquinone from Halorosellinia sp., induces apoptosis in primary human NFPA cells via Akt pathway inhibition [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdditionally, shared overexpressed membrane proteins may serve as differential markers between normal and adenoma cells and offer targets for broad-spectrum therapies. Molecular docking results suggest several plant-based compounds and small molecules may inhibit key NFPA proteins such as FOLR1, GRIK1, and TLN1, supporting their potential as therapeutic leads (Tables\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFurthermore, drug repositioning\u0026mdash;repurposing existing drugs for new indications\u0026mdash;may offer viable strategies. For example, the anti-breast cancer agent Mirvetuximab soravtansine, which targets FOLR1, could potentially be repurposed for NFPA treatment [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eDistinct groups of cell membrane proteins are potential targets for tumor detection or targeted drug delivery to tumor cells. \u0026nbsp;However, treatment of solid tumors is challenging, especially for those with very high tumor heterogeneity. Therefore, targeting specific cell membrane proteins could improve pharmaceutical treatments of these tumors. Further clinical research is necessary to validate these findings and translate them into effective treatments for patients with pituitary adenomas.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Iran University of Medical Sciences (Grant No. IR.IUMS.REC.1398.632). The authors gratefully acknowledge this support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGrant No. IR.IUMS.REC.1398.632\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIR.IUMS.REC.1398.632\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.H designed the work. N.H and YB performed bioinformatics analyses. \u0026nbsp;MH and N.H, interpreted the result. N.H wrote the manuscript. M.H and N.H revised the final version of manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePublicly available datasets were analyzed in this study. The data are openly available in NCBI (GEO DataSets).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eImani, M., et al., \u003cem\u003eComparison of cabergoline versus raloxifene add-on therapy to long-acting somatostatin analogue in patients with inadequately controlled acromegaly: A randomized open label clinical trial.\u003c/em\u003e Endocrine Practice, 2018. \u003cstrong\u003e24\u003c/strong\u003e(6): p. 542-547.\u003c/li\u003e\n\u003cli\u003eMiermeister, C.P., et al., \u003cem\u003eHistological criteria for atypical pituitary adenomas\u0026ndash;data from the German pituitary adenoma registry suggests modifications.\u003c/em\u003e Acta neuropathologica communications, 2015. \u003cstrong\u003e3\u003c/strong\u003e(1): p. 1-11.\u003c/li\u003e\n\u003cli\u003eGhadir, M., et al., \u003cem\u003eCell proliferation, apoptosis, and angiogenesis in non-functional pituitary adenoma: association with tumor invasiveness.\u003c/em\u003e Endocrine, 2020. \u003cstrong\u003e69\u003c/strong\u003e(3): p. 596-603.\u003c/li\u003e\n\u003cli\u003eAboregela, A.M., \u003cem\u003eApproaches based on natural products and miRNAs in pituitary adenomas: unveiling therapeutic intervention.\u003c/em\u003e Naunyn-Schmiedeberg\u0026apos;s Archives of Pharmacology, 2025. \u003cstrong\u003e398\u003c/strong\u003e(1): p. 69-88.\u003c/li\u003e\n\u003cli\u003ePeng, J., et al., \u003cem\u003eComprehensive transcriptomic analysis identifies three distinct subtypes of pituitary adenomas: insights into tumor behavior, prognosis, and stem cell characteristics.\u003c/em\u003e Journal of Translational Medicine, 2024. \u003cstrong\u003e22\u003c/strong\u003e(1): p. 892.\u003c/li\u003e\n\u003cli\u003eGrimm, D., et al., \u003cem\u003eDiagnostic and therapeutic use of membrane proteins in cancer cells.\u003c/em\u003e Current medicinal chemistry, 2011. \u003cstrong\u003e18\u003c/strong\u003e(2): p. 176-190.\u003c/li\u003e\n\u003cli\u003eHe, B., et al., \u003cem\u003eASGARD is a single-cell guided pipeline to aid repurposing of drugs.\u003c/em\u003e Nature Communications, 2023. \u003cstrong\u003e14\u003c/strong\u003e(1): p. 993.\u003c/li\u003e\n\u003cli\u003eWu, H., et al., \u003cem\u003eGenetic and Functional Changes in Mitochondria in the Pituitary Adenoma: The Pathogenesis and Its Therapy.\u003c/em\u003e Antioxidants, 2024. \u003cstrong\u003e13\u003c/strong\u003e(12): p. 1514.\u003c/li\u003e\n\u003cli\u003eLyu, L., et al., \u003cem\u003eAutophagy inhibition enhances anti‐pituitary adenoma effect of tetrandrine.\u003c/em\u003e Phytotherapy Research, 2021. \u003cstrong\u003e35\u003c/strong\u003e(7): p. 4007-4021.\u003c/li\u003e\n\u003cli\u003eBoonstra, M.C., et al., \u003cem\u003eSelecting targets for tumor imaging: an overview of cancer-associated membrane proteins.\u003c/em\u003e Biomarkers in cancer, 2016. \u003cstrong\u003e8\u003c/strong\u003e: p. BIC. S38542.\u003c/li\u003e\n\u003cli\u003eXu, Q., et al., \u003cem\u003eIsolation of tumour stem-like cells from benign tumours.\u003c/em\u003e British journal of cancer, 2009. \u003cstrong\u003e101\u003c/strong\u003e(2): p. 303-311.\u003c/li\u003e\n\u003cli\u003eZhu, L., et al., \u003cem\u003eEvidence of CD90+ CXCR4+ cells as circulating tumor stem cells in hepatocellular carcinoma.\u003c/em\u003e Tumor Biology, 2015. \u003cstrong\u003e36\u003c/strong\u003e(7): p. 5353-5360.\u003c/li\u003e\n\u003cli\u003eYamashita, T., et al., \u003cem\u003eDiscrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma.\u003c/em\u003e Hepatology, 2013. \u003cstrong\u003e57\u003c/strong\u003e(4): p. 1484-1497.\u003c/li\u003e\n\u003cli\u003eOhga, N., et al., \u003cem\u003eHeterogeneity of tumor endothelial cells: comparison between tumor endothelial cells isolated from high-and low-metastatic tumors.\u003c/em\u003e The American journal of pathology, 2012. \u003cstrong\u003e180\u003c/strong\u003e(3): p. 1294-1307.\u003c/li\u003e\n\u003cli\u003eAvril, T., E. Vauleon, and E. Chevet, \u003cem\u003eEndoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers.\u003c/em\u003e Oncogenesis, 2017. \u003cstrong\u003e6\u003c/strong\u003e(8): p. e373-e373.\u003c/li\u003e\n\u003cli\u003eZhao, Y., \u003cem\u003eThe oncogenic functions of nicotinic acetylcholine receptors.\u003c/em\u003e Journal of oncology, 2016. \u003cstrong\u003e2016\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eLuo, C. and J. Shen, \u003cem\u003eAdducin in tumorigenesis and metastasis.\u003c/em\u003e Oncotarget, 2017. \u003cstrong\u003e8\u003c/strong\u003e(29): p. 48453.\u003c/li\u003e\n\u003cli\u003ePerot, B.P. and M.M. M\u0026eacute;nager, \u003cem\u003eTetraspanin 7 and its closest paralog tetraspanin 6: membrane organizers with key functions in brain development, viral infection, innate immunity, diabetes and cancer.\u003c/em\u003e Medical Microbiology and Immunology, 2020. \u003cstrong\u003e209\u003c/strong\u003e: p. 427-436.\u003c/li\u003e\n\u003cli\u003eDetchokul, S., et al., \u003cem\u003eTetraspanins as regulators of the tumour microenvironment: implications for metastasis and therapeutic strategies.\u003c/em\u003e British journal of pharmacology, 2014. \u003cstrong\u003e171\u003c/strong\u003e(24): p. 5462-5490.\u003c/li\u003e\n\u003cli\u003eChen, Y., et al., \u003cem\u003eGenomic and transcriptomic analysis of pituitary adenomas reveals the impacts of copy number variations on gene expression and clinical prognosis among prolactin-secreting subtype.\u003c/em\u003e Aging (Albany NY), 2021. \u003cstrong\u003e13\u003c/strong\u003e(1): p. 1276.\u003c/li\u003e\n\u003cli\u003eBisgin, A., et al., \u003cem\u003eInteraction of CD200 overexpression on tumor cells with CD200R1 overexpression on stromal cells: an escape from the host immune response in rectal cancer patients.\u003c/em\u003e Journal of oncology, 2019. \u003cstrong\u003e2019\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eHoriguchi, K., et al., \u003cem\u003eCX3CL1/CX3CR1-signalling in the CD9/S100\u0026beta;/SOX2-positive adult pituitary stem/progenitor cells modulates differentiation into endothelial cells.\u003c/em\u003e Histochemistry and cell biology, 2020. \u003cstrong\u003e153\u003c/strong\u003e(6): p. 385-396.\u003c/li\u003e\n\u003cli\u003eChamera, K., et al., \u003cem\u003eThe prenatal challenge with lipopolysaccharide and polyinosinic: polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: A link to schizophrenia-like behaviours.\u003c/em\u003e Journal of neuroinflammation, 2020. \u003cstrong\u003e17\u003c/strong\u003e(1): p. 1-24.\u003c/li\u003e\n\u003cli\u003eBoresowicz, J., et al., \u003cem\u003eDNA methylation influences mirna expression in gonadotroph pituitary tumors.\u003c/em\u003e Life, 2020. \u003cstrong\u003e10\u003c/strong\u003e(5): p. 59.\u003c/li\u003e\n\u003cli\u003eSui, X., et al., \u003cem\u003eCalcium channel \u0026alpha;2\u0026delta;1 subunit (CACNA2D1) enhances radioresistance in cancer stem-like cells in non-small cell lung cancer cell lines.\u003c/em\u003e Cancer management and research, 2018. \u003cstrong\u003e10\u003c/strong\u003e: p. 5009.\u003c/li\u003e\n\u003cli\u003eHwang, S.-M., et al., \u003cem\u003eThe role of TRP channels and PMCA in brain disorders: intracellular calcium and pH homeostasis.\u003c/em\u003e Frontiers in Cell and Developmental Biology, 2021. \u003cstrong\u003e9\u003c/strong\u003e: p. 57.\u003c/li\u003e\n\u003cli\u003eMartyniuk, C.J., et al., \u003cem\u003eGenomic and proteomic responses to environmentally relevant exposures to dieldrin: indicators of neurodegeneration?\u003c/em\u003e Toxicological Sciences, 2010. \u003cstrong\u003e117\u003c/strong\u003e(1): p. 190-199.\u003c/li\u003e\n\u003cli\u003eHoriguchi, K., et al., \u003cem\u003eExpression of the proteoglycan syndecan-4 and the mechanism by which it mediates stress fiber formation in folliculostellate cells in the rat anterior pituitary gland.\u003c/em\u003e Journal of endocrinology, 2012. \u003cstrong\u003e214\u003c/strong\u003e(2): p. 199.\u003c/li\u003e\n\u003cli\u003eHuang, C.-P., et al., \u003cem\u003eSyndecan-4 promotes epithelial tumor cells spreading and regulates the turnover of PKC\u0026alpha; Activity under mechanical stimulation on the elastomeric substrates.\u003c/em\u003e Cellular Physiology and Biochemistry, 2015. \u003cstrong\u003e36\u003c/strong\u003e(4): p. 1291-1304.\u003c/li\u003e\n\u003cli\u003eNecela, B.M., et al., \u003cem\u003eFolate receptor-\u0026alpha; (FOLR1) expression and function in triple negative tumors.\u003c/em\u003e PloS one, 2015. \u003cstrong\u003e10\u003c/strong\u003e(3): p. e0122209.\u003c/li\u003e\n\u003cli\u003eEvans, C.O., et al., \u003cem\u003eFolate receptor expression in pituitary adenomas: cellular and molecular analysis.\u003c/em\u003e Vitamins \u0026amp; Hormones, 2008. \u003cstrong\u003e79\u003c/strong\u003e: p. 235-266.\u003c/li\u003e\n\u003cli\u003eLarysz, D., et al., \u003cem\u003eExpression of genes FOLR1, BAG1 and LAPTM4B in functioning and non-functioning pituitary adenomas.\u003c/em\u003e Folia neuropathologica, 2012. \u003cstrong\u003e50\u003c/strong\u003e(3): p. 277-286.\u003c/li\u003e\n\u003cli\u003eHonda, M., et al., \u003cem\u003eInhibition of receptor activity\u0026ndash;modifying protein 1 suppresses the development of endometriosis and the formation of blood and lymphatic vessels.\u003c/em\u003e Journal of cellular and molecular medicine, 2020. \u003cstrong\u003e24\u003c/strong\u003e(20): p. 11984-11997.\u003c/li\u003e\n\u003cli\u003eZhang, Q., et al., \u003cem\u003eThe influence of receptor activity\u0026ndash;modifying protein‐1 overexpression on angiogenesis in mouse brain capillary endothelial cells.\u003c/em\u003e Journal of cellular biochemistry, 2019. \u003cstrong\u003e120\u003c/strong\u003e(6): p. 10087-10096.\u003c/li\u003e\n\u003cli\u003eCarulli, D., F. De Winter, and J. Verhaagen, \u003cem\u003eSemaphorins in Adult Nervous System Plasticity and Disease.\u003c/em\u003e Frontiers in synaptic neuroscience, 2021. \u003cstrong\u003e13\u003c/strong\u003e: p. 20.\u003c/li\u003e\n\u003cli\u003eNeufeld, G., et al., \u003cem\u003eThe role of the semaphorins in cancer.\u003c/em\u003e Cell Adhesion \u0026amp; Migration, 2016. \u003cstrong\u003e10\u003c/strong\u003e(6): p. 652-674.\u003c/li\u003e\n\u003cli\u003eDing, Y., et al., \u003cem\u003eSemaphorin 4F as a critical regulator of neuroepithelial interactions and a biomarker of aggressive prostate cancer.\u003c/em\u003e Clinical Cancer Research, 2013. \u003cstrong\u003e19\u003c/strong\u003e(22): p. 6101-6111.\u003c/li\u003e\n\u003cli\u003e\u003cem\u003eUniProt: the universal protein knowledgebase in 2021.\u003c/em\u003e Nucleic Acids Research, 2021. \u003cstrong\u003e49\u003c/strong\u003e(D1): p. D480-D489.\u003c/li\u003e\n\u003cli\u003eTang, X.X., et al., \u003cem\u003eHigh-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas.\u003c/em\u003e Clinical Cancer Research, 1999. \u003cstrong\u003e5\u003c/strong\u003e(6): p. 1491-1496.\u003c/li\u003e\n\u003cli\u003eTang, X.X., et al., \u003cem\u003eImplications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma.\u003c/em\u003e Proceedings of the National Academy of Sciences, 2000. \u003cstrong\u003e97\u003c/strong\u003e(20): p. 10936-10941.\u003c/li\u003e\n\u003cli\u003eHu, C., et al., \u003cem\u003eThe expression of ADAM23 and its correlation with promoter methylation in non‐small‐cell lung carcinoma.\u003c/em\u003e International journal of experimental pathology, 2011. \u003cstrong\u003e92\u003c/strong\u003e(5): p. 333-339.\u003c/li\u003e\n\u003cli\u003eCosta, E., et al., \u003cem\u003eIntratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals.\u003c/em\u003e Oncogene, 2015. \u003cstrong\u003e34\u003c/strong\u003e(10): p. 1270-1279.\u003c/li\u003e\n\u003cli\u003eMunkley, J., et al., \u003cem\u003eThe cancer-associated cell migration protein TSPAN1 is under control of androgens and its upregulation increases prostate cancer cell migration.\u003c/em\u003e Scientific reports, 2017. \u003cstrong\u003e7\u003c/strong\u003e(1): p. 1-11.\u003c/li\u003e\n\u003cli\u003eZemkova, H., et al., \u003cem\u003eMultiple cholinergic signaling pathways in pituitary gonadotrophs.\u003c/em\u003e Endocrinology, 2013. \u003cstrong\u003e154\u003c/strong\u003e(1): p. 421-433.\u003c/li\u003e\n\u003cli\u003eSmith, R.M., et al., \u003cem\u003eNicotinic \u0026alpha; 5 receptor subunit mRNA expression is associated with distant 5\u0026prime; upstream polymorphisms.\u003c/em\u003e European Journal of Human Genetics, 2011. \u003cstrong\u003e19\u003c/strong\u003e(1): p. 76-83.\u003c/li\u003e\n\u003cli\u003eFanlo Escudero, L., \u003cem\u003eNeuroblastoma cancer stem cells: The role of NXPH1 and its receptor \u0026alpha;-NRXN1.\u003c/em\u003e 2019.\u003c/li\u003e\n\u003cli\u003eTaniguchi-Ponciano, K., et al., \u003cem\u003eTranscriptome and methylome analysis reveals three cellular origins of pituitary tumors.\u003c/em\u003e Scientific reports, 2020. \u003cstrong\u003e10\u003c/strong\u003e(1): p. 1-11.\u003c/li\u003e\n\u003cli\u003eRipka, S., et al., \u003cem\u003eGlutamate receptor GRIA3\u0026mdash;target of CUX1 and mediator of tumor progression in pancreatic cancer.\u003c/em\u003e Neoplasia, 2010. \u003cstrong\u003e12\u003c/strong\u003e(8): p. 659-IN6.\u003c/li\u003e\n\u003cli\u003eZhang, C., et al., \u003cem\u003eMicroRNAs Regulated Brain Tumor Cell Phenotype and Their Therapeutic Potential\u003c/em\u003e. 2013: IntechOpen.\u003c/li\u003e\n\u003cli\u003eTatti, O., et al., \u003cem\u003eMMP16 mediates a proteolytic switch to promote cell\u0026ndash;cell adhesion, collagen alignment, and lymphatic invasion in melanoma.\u003c/em\u003e Cancer research, 2015. \u003cstrong\u003e75\u003c/strong\u003e(10): p. 2083-2094.\u003c/li\u003e\n\u003cli\u003eZhang, L.-y., et al., \u003cem\u003eFibroblasts play a potential role in bone destruction via osteopontin related caldesmon expression and polymerization in human non-functioning pituitary adenomas.\u003c/em\u003e Scientific reports, 2017. \u003cstrong\u003e7\u003c/strong\u003e(1): p. 1-10.\u003c/li\u003e\n\u003cli\u003eVargas-Ortega, G., B. Gonzalez-Virla, and C.A. Romero-Gameros, \u003cem\u003ePharmacological treatment of non-functioning pituitary adenomas.\u003c/em\u003e Archives of Medical Research, 2023. \u003cstrong\u003e54\u003c/strong\u003e(8): p. 102917.\u003c/li\u003e\n\u003cli\u003eWang, X., et al., \u003cem\u003eThe marine metabolite SZ-685C induces apoptosis in primary human nonfunctioning pituitary adenoma cells by inhibition of the Akt pathway in vitro.\u003c/em\u003e Marine drugs, 2015. \u003cstrong\u003e13\u003c/strong\u003e(3): p. 1569-1580.\u003c/li\u003e\n\u003cli\u003eZamami, Y., et al., \u003cem\u003eDrug-repositioning approaches based on medical and life science databases.\u003c/em\u003e Frontiers in Pharmacology, 2021. \u003cstrong\u003e12\u003c/strong\u003e: p. 752174.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1:\u003c/strong\u003e Series IDs, number of samples, subtypes of PAs, and microarray platform of datasets.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeries ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of samples\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePA subtypes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlatform\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGSE119063\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e5 PRL, 4 normal human pituitaries\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAgilent\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGSE93825\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e40 ACTH secreting PA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eIllumina Human HT-12 WG-DASL V4.0 R2 expression bead chip\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGSE63357\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e13 GH secreting PA, 7 non-functioning PA, 5 normal human pituitary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAffymetrix\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGSE51618\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e4 non-Invasive non-functioning PA, 3 Invasive non-functioning PA, 3 normal human pituitary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAgilent\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGSE36314\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e4 PRL, 3 normal human pituitary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAffymetrix\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGSE26966\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e14 Null, 9 normal human pituitary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAffymetrix\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGSE2175\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e1 non-functioning PA, 1 ACTH secreting PA, 1 GH secreting PA, 1 PRL, 1 normal human pituitary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eAffymetrix\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGSE22812\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 198px;\"\u003e\n \u003cp\u003e6 Aggressive-Invasive, 2 Invasive, and 5 non-Invasive PRL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eGE Healthcare/Amersham BiosciencesCodelink Human whole Genome Bioarray\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u003c/strong\u003e Comparison of groups and the number of shared deregulated genes with one or more subtypes.\u003c/p\u003e\n\u003cp\u003eThe number of exclusively deregulated genes in each comparison group is shown in parentheses.\u003c/p\u003e\n\u003cp\u003e\u0026ldquo;no\u0026rdquo; indicates that no exclusive deregulated genes were identified in that group..\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComparing groups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e# Down-regulated genes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e# Up-regulated genes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eACTH Vs. normal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e97(no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e64(1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGH Vs. normal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e151(8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e89(62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInvasive NFPA Vs. Non-invasive NFPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e2(2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e2(2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInvasive NFPA Vs. normal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e129(22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e51(21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNFPA Vs. normal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e377(74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e348(185)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-Invasive Vs. normal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e194(13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e99(5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNull Vs. normal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e359(27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e120(1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePRL Vs. normal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e240(9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e27(no)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 259px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMerged NFPA (with NFPA, Invasive NFPA, and non-invasive NFPA labels) Vs. normal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 173px;\"\u003e\n \u003cp\u003e299(1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e167(no)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3:\u003c/strong\u003e Shared DEGs among all types of PA.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymbol \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFunction\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdenoma type (log\u003csub\u003e2\u003c/sub\u003eFC)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFILIP1l (up)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eFilaminA Interacting Protein 1 Like\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eRegulator of the antiangiogenic activity, Leads to inhibition of cell proliferation and migration and an increase in apoptosis \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eGH (0.76), PRL (1.06), ACTH (1.07), NFPA (1.17), NULL (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eISRL (down)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eImmunoglobulin Superfamily Containing Leucine Rich Repeat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eMainly localized to the plasma membrane\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eGH (-1.6), PRL (-1.8), ACTH ( -1.2), NFPA (-1.73), NULL ( -1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4:\u003c/strong\u003e Gene ontology of up-regulated PA type-specific targets.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 91px;\"\u003e\u003cstrong\u003eAdenoma type\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 162px;\"\u003e\u003cstrong\u003eType specific up-regulated cell membrane proteins\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 71.7158%;\"\u003e\u003cstrong\u003eFunction\u003c/strong\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGH\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTHY1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCell adhesion and cell communication\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCHRNA3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eLigand-gated ion channel, neurotransmission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIGSF6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eTransmembrane signaling receptor activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSLC26A4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eChloride transmembrane transporter activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNFPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCX3CR1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eAdhesion and migration of leukocytes\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCNIH3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eRegulating trafficking and gating properties of glutamate receptors, opioid dependence, voltage-gated calcium channel activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCD200\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eHave a role in immunosuppression and regulation of anti-tumor activity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFOLR1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eTransports 5-methyltetrahydrofolate into cells\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRAMP1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eRequired to transport calcitonin-receptor-like receptor to the plasma membrane, terminal glycosylation, maturation, and presentation of the CGRP receptor to the cell surface, neural development\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eATP2B1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eIntracellular calcium homeostasis, cAMP signaling, and cGMP-PKG signaling pathways \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEFNB3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eLigand for Eph receptors, crucial for migration, repulsion, and adhesion during neuronal, vascular, and epithelial development\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eADAM23\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eCell-cell and cell-matrix interactions, involved in fertilization, muscle development, and neurogenesis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTSPAN1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003esignal transduction, cell development, activation, growth, and motility\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCHRNA5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eMember of a superfamily of ligand-gated ion channels mediating fast signal transmission at synapses\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSDC4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eBelongs to Heparan sulfate proteoglycans family\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNRXN1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003eRequired for efficient neurotransmission, involved in the formation of synaptic contacts, cell-cell-interactions, exocytosis of secretory granules, and the regulation of signal transmission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eInvasive NFPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGRIK1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePredominant excitatory neurotransmitter receptors in the mammalian brain, involved in the normal neurophysiologic process\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGRIA3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003ePredominant excitatory neurotransmitter receptors in the mammalian brain, involved in the normal neurophysiologic process\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eATP2B2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003ePlays a critical role in intracellular calcium homeostasis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMMP16\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eInvolved in the breakdown of extracellular matrix in embryonic development, reproduction, and tissue remodeling, cancer development, progression, and metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 91px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNon-invasive NFPA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTLN1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eInvolved in the attachment of adherent cells to extracellular matrices and of lymphocytes to other cells\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5:\u0026nbsp;\u003c/strong\u003eBinding Affinity of Plant-Derived Compounds with FOLR1, GRIK1 and TLN1.\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable dir=\"rtl\" border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"607\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBinding\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAffinity\u003c/strong\u003e\u003cstrong\u003e(kcal/mol)\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCompound name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eLigand (PubChem ID)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 607px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eFOLR1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-11.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e53522790\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-11.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e11936\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-11.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e91742606\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e101609000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003e4-o-caffeoylshikimic acid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e49821869\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-10.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eFLAVONE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e10680\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-10.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e69531189\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-10.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e91744068\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-10.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eGeranial oxypeucedaninyl acetal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e91750110\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-10.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e101608999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 607px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eGRIK1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-10.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eDESGLUCORUSCIN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e90471987\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-10.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eLuteolin 7-rutinoside\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e44258082\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-9.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e53788517\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-9.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eLMPK12111861\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e44258931\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-9.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e101693312\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-9.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eHesperidin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e10621\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-9.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eCannabisin-D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e71448965\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-9.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e102444811\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-9.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e90473944\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-9.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003emalvidin 3-O-rutinoside\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e90657906\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 607px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eTLN1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eOleanolic Acid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e10494\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eBicyclomahanimbicine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e77994099\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e101280261\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e101608999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e53788517\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e90473944\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eSynthetic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e101609000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eMurrayazolinine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e101856126\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eMudanpioside H\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e71457654\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp dir=\"LTR\"\u003eCholane-5,20(22)-diene-3b-phenoxy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 191px;\"\u003e\n \u003cp dir=\"LTR\"\u003e91742606\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp dir=\"RTL\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 6\u003c/strong\u003e: Binding Affinity of Small Molecules with FOLR1 and GRIK1\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable dir=\"rtl\" border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"534\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBinding Affinity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCompound name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eLigand (PubChem ID)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 534px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 534px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eFOLR1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-9.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp dir=\"LTR\"\u003eONX0801\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e135487419\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 534px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eGRIK1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp dir=\"LTR\"\u003eLY466195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e9935648\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp dir=\"LTR\"\u003eACET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e16125102\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-8.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp dir=\"LTR\"\u003eNBQX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e3272524\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-7.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp dir=\"LTR\"\u003eCNQX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e3721046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-7.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp dir=\"LTR\"\u003eDNQX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e3899541\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-7.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp dir=\"LTR\"\u003eUBP302\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e6420161\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42px;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e-7.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp dir=\"LTR\"\u003eUBP310\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp dir=\"LTR\"\u003e6420160\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pituitary adenoma, Gene expression, Diagnostic-therapeutic biomarkers, plant-derived compounds, small molecules, therapeutic strategies","lastPublishedDoi":"10.21203/rs.3.rs-7604876/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7604876/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003ePituitary adenomas (PAs) account for 10\u0026ndash;15% of intracranial neoplasms. Although generally benign, many PAs, especially non-functional types lack effective medical treatments. Cell membrane proteins are promising targets for diagnosis and therapy due to their accessibility and specificity. This study aimed to identify shared and subtype-specific deregulated membrane proteins across PA types and evaluate the potential of natural compounds and small molecules to inhibit these targets.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eEight microarray datasets comprising 77 PA and 25 normal pituitary samples were analyzed using the Limma package in R version 4.3.0. Batch effects were removed with ComBat. Differentially expressed genes (DEGs) were identified and filtered for membrane proteins. Functional annotation was performed using EnrichR. Structures of key proteins were retrieved from PDB/AlphaFold and docked with plant-derived compounds and small molecules using PyRx.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFILIP1L (upregulated) and ISRL (downregulated) were identified as shared membrane protein targets across all PA subtypes. Subtype-specific upregulated membrane proteins included THY1 (GH), ADD1 and TSPAN6 (PRL), and CX3CR1, FOLR1, and RAMP1 (NFPA). Docking analysis highlighted strong binding affinities between several natural compounds and proteins FOLR1, GRIK1, and TLN1. The FDA-approved drug Mirvetuximab soravtansine also showed potential in targeting FOLR1.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eSubtype-specific and shared membrane proteins in PAs represent viable diagnostic and therapeutic targets. Natural compounds and repurposed drugs may offer new treatment strategies, particularly for non-functional and invasive PAs.\u003c/p\u003e","manuscriptTitle":"Transcriptomic landscape of Pituitary Adenomas: potential diagnostic and therapeutic targets","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-24 14:21:16","doi":"10.21203/rs.3.rs-7604876/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"74b2f756-beec-4224-80f7-b38b1ce5ee6b","owner":[],"postedDate":"September 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-06T09:56:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-24 14:21:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7604876","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7604876","identity":"rs-7604876","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}