Cartilage Oligomeric Matrix Protein in Pulmonary Arterial Hypertension Associated with Lung Adenocarcinoma

Cartilage Oligomeric Matrix Protein in Pulmonary Arterial Hypertension Associated with Lung Adenocarcinoma | 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 Cartilage Oligomeric Matrix Protein in Pulmonary Arterial Hypertension Associated with Lung Adenocarcinoma DONGQING YAN, Bangxian Hu, Shan Jiang, Jun Hang Zhang, Yun Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7848534/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Objective Pulmonary arterial hypertension (PAH) associated with lung adenocarcinoma(LUAD) is a pathological state that emerges during LUAD progression. Cartilage oligomeric matrix protein (COMP) is an important extracellular matrix (ECM) glycoprotein and may be an independent prognostic biomarker. Methods We collected chest enhanced CT scans from clinical LUAD patients, screen PAH based on the PA/A ratio. By analyzing the TCGA-LUAD, GSE140797 and VSMCPRG gene sets, we identified the gene sets related to PAH in LUAD.Additional, we analysis of pathological samples, serum samples, EdU cell proliferation assays, and measurements of pulmonary artery vascular contraction functions. Results 421 clinical patients were enrolled in this study.In the LUAD group ,the PA/A ratio ≥ 1 is significantly higher compared to both the Adenocarcinoma In Situ(AIS) group and the Benign nodule group.17 pathological samples revealed a significant upregulation of COMP in LUAD group compared to normal lung tissue.Serum samples showed significantly higher optical density (OD) values in the LUAD group compared to the other group.EdU experiment demonstrated that human pulmonary artery smooth muscle cells (HPASMC) co-cultured with COMP exhibited significantly higher proliferation rates compared to the control group.To assessing the effect of COMP on pulmonary artery vasculature, rat and human experiments indicated that the contraction force of the COMP group was significantly higher than that of the control group. Conclusions The findings suggest that LUAD patients may be associated with PAH, COMP may promote the development of PAH by enhancing the proliferation of pulmonary artery smooth muscle cells and the contractile function of pulmonary artery vessels. COMP LUAD PAH PA/A Ratio Bioinformatics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Many early-stage LUAD patients often present without noticeable symptoms, However, recent studies have shown that some patients do exhibit symptoms during the early stages of lung cancer. For instance, a study by Sarah Sharman Moser et al [ 1 ] ,involving 302 patients found that 79.5% of patients reported at least one symptom, with 12.3% reporting four or more symptoms. As the tumor progresses to later stages, symptoms vary among individuals. Therefore, symptoms such as coughing and shortness of breath may be present at different stages of lung cancer [ 2 ] . It is still not clear whether these symptoms are related to LUAD and PAH. Method Clinical Patient Data Collection Data were collected from patients who underwent surgery between 2018 and 2023 in my department. We measured the ratio of PA/A from their preoperative chest CT. The inclusion criteria were as follows:1.Patients with a pathological diagnosis of lung adenocarcinoma, with stage from I-IV;2.Patients with a pathological diagnosis of AIS;3. The pathological diagnosis was inflammatory nodules and (AAH);4.No history of smoking or alcohol consumption;5.No history of hypertension, diabetes, or other tumor history.A total of 421 patients were included in the study, with 226 patients in the LUAD group, 116 patients in the AIS group, and 79 patients in the Benign nodule group. Measurement of PA/A ratio The PA/A ratio is measured through imaging using chest enhanced CT to determine the ratio of the diameter of the pulmonary artery (PA) to the diameter of the aorta (A). Normally, the diameter of the PA should be less than or equal to the diameter of the A, with a PA/A ratio typically ≤ 1. If the PA/A ratio is greater than 1, it may indicate PAH [ 3 , 4 ] . Data Collection for Bioinformatics Analysis The TCGA-LUAD database includes 584 samples with 58,385 gene expressions. In contrast, the GEO database, GSE140797, comprises 14 samples (7 pairs of lung adenocarcinoma and normal tissues) with 29,834 gene expressions. The VSMCPRG dataset was obtained through literature review and includes 356 genes, of which 338 were annotated via Gene Ontology, and 18 were identified through literature searches [ 5 ] . Pathological Paraffin Sample Collection A total of 17 paraffin-embedded samples were collected and divided into three groups: 5 cases of LUAD, 5 cases of AIS, and 7 cases of Benign nodules. For each patient, one sample of the lung lesion tissue and one sample of the adjacent normal tissue were collected. These samples were subjected to immunohistochemical (IHC) staining for the COMP antigen. The staining intensity was categorized as follows: no positive staining (negative), light yellow staining (weak positive), brownish yellow staining (positive), and brown staining (strong positive) [ 6 – 8 ] . Serum Sample Collection A total of 65 serum samples were collected. The LUAD group included 25 samples from patients with stages I to IV. The AIS group and the the Benign nodule group each included 20 samples, totaling 40 samples. EdU Cell Proliferation Assay EdU (5-ethynyl-2'-deoxyuridine) is a thymidine deoxynucleotide analog that can be incorporated into newly synthesized DNA during DNA replication. In this experiment, recombinant COMP protein was co-cultured with HPASMC. Detection of COMP on Pulmonary Artery Vasoconstriction This study verified the effect of COMP on pulmonary artery vasoconstriction through two sets of experiments using both rat and human pulmonary arteries. The DMT 620M myograph instrument was used to measure the changes in vascular contraction. Result Table 1 *Indicates statistical significance, with p < 0.05. From the Table 1 , we observed significant differences in patient age, with most patients over 60 years old concentrated in the LUAD group.Regarding gender, the proportion of females was significantly higher, consistent with previous reports showing that females have the highest incidence of lung adenocarcinoma [ 9 – 10 ] . For PA/A values ≥ 1, the LUAD group had significantly higher PA/A values ≥ 1 compared to the AIS group and the Benign nodule group, with statistically significant differences. Bioinformatics Data Analysis The TCGA-LUAD (1198 genes), GSE140797 (269 genes), and VSMCPRG (356 genes) gene sets were all plotted as Venny diagrams using the Venny 2.1 network tool. Six differentially expressed genes were identified:MDK, COL1A1, COL3A1, PITX2, SIX1, and COMP.Subsequently, we performed pathway enrichment analysis on these six differential genes and created a bubble plot.After reviewing relevant literature [ 11 – 13 ] , we found that the (GO:0030199) was the most relevant to our study. The genes involved in this pathway include COL1A1, COMP, and COL3A1.Given the roles of these genes in maintaining vascular contractile phenotype and their effects on collagen proteins, we hypothesized that COMP might be a key gene involved in the PAH associated with LUAD [ 14 – 15 ] . Using the gene search function on the GEPIA platform, The results showed that COMP is widely distributed in the lungs, bile ducts, bones, and blood vessels. In disease states, COMP expression was significantly higher in lung adenocarcinoma, cholangiocarcinoma, breast cancer, and aortic diseases compared to normal tissues. Subsequently, we performed survival prognosis analysis of COMP and the results indicated no statistically significant difference between the high-expressing and low-expressing groups. Pathological Paraffin-embedded Samples Data Analysis The mean value for the LUAD group (5.94 ± 2.03) is significantly greater than both the AIS group (2.62 ± 1.36) and the Benign nodule group (1.89 ± 1.12) after statistical analysis, and the difference between AIS and Benign nodule group is not statistically significant. This indicates that the expression of COMP in the extracellular matrix of the LUAD group is significantly higher than in both AIS group and Benign nodule group. Figuer 2 Fig A represents the Benign Nodule Group: ECM of the affected nodules showed no significant positive staining;Fig B represents the AIS Group:The staining of the ECM around the affected nodules was deeper compared to the Benign nodule group, and partial brownish staining was observed;Fig C represents the LUAD Group: A significant increase in brownish staining (positive). The expression of COMP was upregulated around the affected nodules,the pulmonary artery smooth muscle cells exhibited proliferation and thickening. The Results of COMP in Serum Sample The serum samples collected for this study totalled 65 cases.The OD values of each well were measured using an ELISA at a wavelength of 450 nm. Table 2. The OD values measured by COMP . The study included 25 samples of LUAD group with an average OD value of 0.46 ± 0.28, 20 samples of AIS group with an average OD value of 0.26 ± 0.11, and 20 samples of the Benign nodule group with an average OD value of 0.21 ± 0.12. Furthermore, within the LUAD group, the measured OD values were higher for more advanced stages. Specifically, the highest OD values (1.259 and 1.015) were observed in IV and III stage samples, respectively, while OD values for II and I stage lung adenocarcinoma samples were predominantly between 0.2 and 0.7. In contrast, the OD values for AIS samples were primarily between 0.1 and 0.3. For the Benign nodule group, the OD values were mainly between 0.1 and 0.2. The Effect of COMP on Proliferation of HPASMC In this experiment, recombinant COMP protein was co-cultured with HPASMC. The mean value for the experimental groups was 37.50 ± 10.303, while that for the control groups was 26.58 ± 9.464. The experimental groups showed significantly higher cell proliferation compared to the control groups. This suggests that the HPASMC in the experimental groups exhibited significantly higher proliferation when co-cultured with recombinant COMP protein compared to the control groups. Additionally, multiple experimental and control groups were compared using EdU cell proliferation fluorescence imaging, which clearly demonstrated a higher number of proliferating cells in the experimental groups compared to the control groups. The Role of COMP in the Contraction Function of Pulmonary Arteries Detection of Contraction Function in Rat Pulmonary Arteries After isolating and standardizing the rat pulmonary arteries, they were treated with recombinant COMP protein. The experimental group was incubated with 25 ng/ml recombinant COMP protein for 1 hour, while the control group was not treated with recombinant COMP protein. Subsequently, the contraction function of the arteries was measured under the influence of various concentrations of norepinephrine (NE), acetylcholine (Ach), and endothelin-1 (ET-1). The comparison of contraction force values is based on the average values of the measured data. Results and Analysis(Fig. 4 ) Figure A: The cells were incubated for 1 hour, followed by the addition of 10 − 5 mol/L PE to induce initial vasoconstriction, serving as a reference point. Subsequently, the contractile force was measured at Ach concentrations ranging from 10 − 9 to 10 − 5 mol/L. The data points in Figure A represent the percentage of the baseline contractile force. As shown in Figure A, both the experimental and control groups exhibited a gradual decrease in contractile force with increasing Ach concentration. However, the decline in the experimental group was more gradual compared to the control group. Figure B: The contractile force of the experimental group was compared to that of the control group under the action of PE. The linear graph in Figure B indicates that COMP has a weaker effect on vasoconstriction in pulmonary arteries compared to the control group. Figure C: In the group treated with both COMP and ET-1, the contractile force was significantly higher than that of the control group when the ET-1 concentration reached 10 − 8 mol/L. Statistical analysis revealed that the difference between the two groups was significant when the ET-1 concentration reached 10 − 7 mol/L (COMP group: 119.70% > control group: 96.35%, p < 0.05). Detection of Contraction Function in Human Pulmonary Arteries In this study, lung tissue samples were obtained from enrolled patients undergoing lobectomy. A total of 10 patient-derived lobar specimens were included in the experiments. Drug Incubation Protocol To minimize inter-individual variability, vessels from the same patient were used as self-controlled pairs, divided into experimental and control groups. The experimental group was incubated with recombinant COMP protein (25 ng/mL) for 1 hour, while the control group received no COMP treatment.In preliminary tests, human pulmonary arteries exhibited low sensitivity to PE stimulation, precluding reliable quantification of contractile responses. Consequently, ACh incubation was omitted in subsequent experiments.Finally, contractile responses of both groups were measured across a gradient of ET-1 concentrations to evaluate concentration-dependent effects. Analysis revealed that COMP-treated vessels exhibited significantly greater contractile responses to ET-1 compared to control vessels. This enhancement became particularly pronounced at an ET-1 concentration of 10 − 7 mol/L(132.71% of baseline vs 72.84% in controls, p = 0.0024). Discussion In healthy individuals, the serum and synovial fluid COMP levels are approximately 5.93 ± 1.95 µg/mL and 33 ± 10 µg/mL [ 16 ] . Recent studies have revealed that COMP plays a critical role in the pathogenesis of various diseases, including malignancies, cardiovascular disorders, and fibrotic conditions [ 17 – 19 ] .Elevated COMP expression has been consistently observed in patients with hepatocellular carcinoma, colorectal cancer, and breast cancer. Additionally, emerging evidence suggests its involvement in prostate cancer, ovarian cancer, and thyroid malignancies [ 20 – 22 ] . Furthermore, COMP plays a significant role in vascular pathologies, including disorders of the pulmonary artery and aorta. PA/A ratio measurement revealed that 53 patients in the LUAD group, 13 in the AIS group, and 8 with the Benign nodules group had a PA/A ratio ≥ 1, Statistical analysis demonstrated a significant difference (p = 0.003), indicating that LUAD had a greater impact on pulmonary hypertension compared to AIS and the Benign nodules. In this study, the PA/A ratio was selected as a radiographic indicator for potential pulmonary hypertension based on the following rationale: First, existing literature suggests that the PA/A ratio is a more reliable non-invasive marker for pulmonary hypertension than the PA diameter alone, as it better correlates with reduced one-year median overall survival [ 4 , 23 ] . Second, the PA/A ratio accounts for individual variations in ascending aortic diameter, thereby minimizing potential confounding factors. We analyzed gene expression profiles from TCGA and GEO, along with a manually curated dataset of VSMCPRG derived from literature mining. Through this approach, COMP emerged as the most relevant candidate for further investigation.Using the GEPIA platform, we first validated the differential expression of COMP between LUAD tissues and normal controls. Our results demonstrated significant upregulation of COMP in LUAD tissues. Intriguingly, COMP was also markedly elevated in vascular disease samples compared to healthy controls, suggesting its potential influence on pulmonary vascular contractile phenotypes. Furthermore, we evaluated the prognostic value of COMP with LUAD patients. The results showed that there was no statistically significant difference between the high COMP expression group and the low COMP expression group (P = 0.54). This might be because patients with early to mid-stage LUAD, after undergoing comprehensive treatments such as surgery, have removed the causes of the cancer and thus have no significant difference in survival prognosis.This observation suggests that LUAD-associated PAH symptoms—such as chest tightness and exertional dyspnea—could be alleviated or masked after standard oncologic treatment. Our study on COMP expression in paraffin-embedded pathological specimens revealed that: Within the extracellular matrix of perinodular pulmonary arteries, COMP expression was significantly higher in the LUAD group compared to both the AIS group and the Benign nodule group, suggesting a potential pathological role in malignant progression.Further analysis demonstrated no significant difference in the Area% values among the three groups in the adjacent peri-nodular tissue, indicating that COMP expression levels in histologically normal tissue were not markedly elevated.These findings indicate that COMP expression exhibits significant variation across different pathological states. Its elevated expression in LUAD tissue appears to be closely associated with the formation and progression of the tumor microenvironment. COMP is an exocrine protein that can be measured in serum samples to determine its expression levels. Statistical analysis revealed significant differences in OD values between the LUAD group and both AIS group and the Benign nodule group. However, no significant statistical difference was observed between AIS group and the Benign nodule group. These findings indicate that the OD values in the LUAD group are significantly higher than those in AIS group and the Benign nodule group. Moreover, the OD value may increase as the tumor stage progresses. However, this result requires more data to be confirmed. The EdU cell proliferation assay demonstrated that COMP promotes the proliferation of HPASMC.Possible mechanisms include: COMP may regulate the expression of cell cycle-related proteins, promoting cells to transition from the G1 phase to the S phase, thereby increasing cell proliferation.COMP may inhibit apoptosis, thereby increasing cell survival rates and promoting cell proliferation.COMP may modulate the composition and structure of the ECM, providing a more favorable microenvironment for cell proliferation. This may also promote the secretion and deposition of ECM by vascular smooth muscle cells, enhancing ECM stability.COMP may promote the proliferation and migration of vascular smooth muscle cells, facilitating vascular remodeling. This is beneficial for vascular growth and repair under physiological conditions but can lead to abnormal vascular remodeling under pathological conditions.Under the stimulation of lung adenocarcinoma cells, COMP levels may increase, leading to enhanced proliferation of HPASMC. In our preliminary studies and literature review, we found that COMP is closely related to the maintenance of the contractile phenotype of blood vessels [ 24 ] . Therefore, if COMP can continue to exert a contractile effect on pulmonary arteries when its expression in the extracellular matrix increases, it would further support its positive role in PAH. We conducted the experiments in animals using rats as the model. PE (10 − 5 mol/L) was added to stimulate the contraction of the pulmonary arteries, serving as the baseline. Next, we added various concentrations of ACh (from 10 − 9 to 10 − 5 mol/L) to observe changes in the contraction force of the pulmonary arteries. Under the action of ACh, the contraction force of the experimental group was higher than that of the control group. However, the difference in contraction force between the two groups was not statistically significant according to the statistical analysis. The results of ET-1 showed that the contraction force of the experimental group gradually exceeded that of the control group when the ET-1 concentration reached 10 − 8 mol/L. Statistical analysis revealed that the difference between the two groups was significant when the ET-1 concentration reached 10 − 7 mol/L (COMP group: 119.70% > control group: 96.35%, p < 0.05). We analyzed that under the influence of ACh, the contraction force of the pulmonary arteries in the COMP group decreased more slowly, indicating that COMP can exert a contractile effect on the pulmonary arteries. Regarding the addition of PE, there was no significant difference in the contraction force between the COMP group and the control group. This may be due to the relatively low concentrations of PE and COMP, which may not have been sufficient to produce a detectable difference in this concentration range. Additionally, PE primarily causes vasoconstriction by selectively activating α-adrenergic receptors, thereby enhancing smooth muscle contraction and increasing vascular resistance and blood pressure. ET-1, on the other hand, increases intracellular calcium ion concentrations by activating ET receptors, leading to smooth muscle contraction [ 25 ] .From this perspective, COMP may share similar mechanisms in causing pulmonary artery contraction with ET-1, which could explain the more pronounced synergistic effect observed in their combined presence. We further tested the effect of COMP on human pulmonary arteries by using human tissue samples. The experimental results showed that under the same concentration of ET-1 stimulation, the contraction force of human pulmonary arteries treated with COMP was significantly higher than that of the control group. In summary, during the development of lung adenocarcinoma, cancer cells stimulate a significant increase in the expression of COMP in the extracellular matrix. COMP further promotes the occurrence of pulmonary hypertension by influencing the proliferation of pulmonary artery vascular smooth muscle cells and enhancing the contraction of pulmonary arteries. Most patients with lung adenocarcinoma may not experience symptoms related to pulmonary hypertension, which may be related to the early stage of cancer or the insufficient attention of clinical doctors. However, during the development of lung adenocarcinoma, the pulmonary artery vessels may already have undergone corresponding pathological and physiological changes. Declarations Conflict of Interest Statement ALL authors disclosed no relevant relationships. Ethical Statement This research has been approved by the ethics committee of our hospital. The name of the ethics committee and institutional review board is the Medical Ethics Committee of the Seventh Affiliated Hospital of Sun Yat-sen University (Shenzhen), and the IRB number is KY-2025-427-01. I confirm that we have obtained the written informed consent from all participants. Funding Declaration There was no Funding in our research. Author Contribution D.Y., B.H.,S.J., J.Z.,Y.L. participated in research design. D.Y., B.H., Y.L. participated in the writing of the paper. D.Y., B.H. participated in the performance of the research. D.Y., B.H.,S.J., J.Z.,Y.L. contributed analytic tools or methods. D.Y., B.H.,S.J., J.Z.,Y.L.participated in data analysis.The authors declare no conflicts of interest and received no funding for this study. 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University","correspondingAuthor":false,"prefix":"","firstName":"Bangxian","middleName":"","lastName":"Hu","suffix":""},{"id":570364079,"identity":"e00110dc-e6f4-4795-9273-973483bc4671","order_by":2,"name":"Shan Jiang","email":"","orcid":"","institution":"The Seventh Affiliated Hospital Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Shan","middleName":"","lastName":"Jiang","suffix":""},{"id":570364080,"identity":"caea0b8e-8447-439c-af2d-a7fcd71ba957","order_by":3,"name":"Jun Hang Zhang","email":"","orcid":"","institution":"The Seventh Affiliated Hospital Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"Hang","lastName":"Zhang","suffix":""},{"id":570364081,"identity":"ffd6fa2e-c1bf-4529-8e75-9bbee40b4fab","order_by":4,"name":"Yun Li","email":"","orcid":"","institution":"The Seventh Affiliated Hospital Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-10-13 11:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7848534/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7848534/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":100360725,"identity":"8f670c90-be04-4780-92bc-636d89e642b5","added_by":"auto","created_at":"2026-01-16 07:41:24","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":863394,"visible":true,"origin":"","legend":"","description":"","filename":"CartilageOligomericMatrixProteininPulmonaryArterialHypertensionAssociatedwithLungAdenocarcinoma.docx","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/5a47a2dc738aec485d50a9fc.docx"},{"id":100361270,"identity":"ea1ff784-c397-4544-b7c8-864c59291dcc","added_by":"auto","created_at":"2026-01-16 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05:34:04","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12846,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/bb9b719804a2966ec651b6b4.png"},{"id":100005485,"identity":"5077ff02-eda5-46a5-87f1-4755e3f8844e","added_by":"auto","created_at":"2026-01-12 05:34:04","extension":"xml","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":87814,"visible":true,"origin":"","legend":"","description":"","filename":"6553b301af4f4b1191cc1c668500dde31structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/cb49e543c8625445f26c35ee.xml"},{"id":100361219,"identity":"ef5a7872-6044-4583-a006-4d1f67ad20f5","added_by":"auto","created_at":"2026-01-16 07:44:41","extension":"html","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97286,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/1cdfb3495f06062451d95274.html"},{"id":100005470,"identity":"499e02fd-2d09-43a7-924e-4b3a4b559adc","added_by":"auto","created_at":"2026-01-12 05:34:03","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":274604,"visible":true,"origin":"","legend":"\u003cp\u003eFig A shows a Venny diagram, six differentially expressed genes; Figure B represents a bubble chart,It selects the KEGG-PATHWAY and BP, CC, and MF signaling pathways from GO pathways;Fig C shows the distribution of COMP in tumors (red) and normal tissues (green).;Fig D shows the differential expression of COMP in lung adenocarcinoma and normal tissues.;Fig E represents the survival prognosis of COMP in the high-expression group and the low-expression group.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/90d40f31710a66779f165804.jpeg"},{"id":100005486,"identity":"ab3e1589-240c-4fbd-ae65-d9f65a301693","added_by":"auto","created_at":"2026-01-12 05:34:04","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":333167,"visible":true,"origin":"","legend":"\u003cp\u003eFig A represents the Benign Nodule Group: ECM of the affected nodules showed no significant positive staining;Fig B represents the AIS Group:The staining of the ECM around the affected nodules was deeper compared to the Benign nodule group, and partial brownish staining was observed；Fig C represents the LUAD Group: A significant increase in brownish staining (positive). The expression of COMP was upregulated around the affected nodules,the pulmonary artery smooth muscle cells exhibited proliferation and thickening.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/b030fe4e68734213500e0333.jpeg"},{"id":100005478,"identity":"32b3f17a-0565-41b1-94a4-bc76bc2821b1","added_by":"auto","created_at":"2026-01-12 05:34:03","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":96860,"visible":true,"origin":"","legend":"\u003cp\u003eFig A shows a comparison of EdU-stained images between the experimental group and the control group;Fig B presents a comparison of EdU-positive cell proliferation between multiple sets of the experimental group and the control group.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/cc147b66232b43d4ad703a33.jpeg"},{"id":100361278,"identity":"3b0a3a7b-4ca2-49b7-b5c1-06eca6a2ca34","added_by":"auto","created_at":"2026-01-16 07:44:50","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":57973,"visible":true,"origin":"","legend":"\u003cp\u003eThe results of the COMP test on the three groups of blood vessels in rats.\u003c/p\u003e","description":"","filename":"floatimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/565444c7403b8220037f446b.jpeg"},{"id":100360776,"identity":"f984dcf4-4c66-40f2-966c-9c873d84990d","added_by":"auto","created_at":"2026-01-16 07:43:43","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":40929,"visible":true,"origin":"","legend":"\u003cp\u003eThe results of the COMP test on human pulmonary artery vessels.\u003c/p\u003e","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/b66352b7d063dc325cde7417.jpeg"},{"id":100380793,"identity":"70128e2c-2b5b-4bec-bbcf-fa7770548398","added_by":"auto","created_at":"2026-01-16 10:34:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1501353,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7848534/v1/55e3caa9-42d4-44b3-aab4-99e9dd5633e7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cartilage Oligomeric Matrix Protein in Pulmonary Arterial Hypertension Associated with Lung Adenocarcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMany early-stage LUAD patients often present without noticeable symptoms, However, recent studies have shown that some patients do exhibit symptoms during the early stages of lung cancer. For instance, a study by Sarah Sharman Moser et al \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e,involving 302 patients found that 79.5% of patients reported at least one symptom, with 12.3% reporting four or more symptoms. As the tumor progresses to later stages, symptoms vary among individuals.\u003c/p\u003e \u003cp\u003eTherefore, symptoms such as coughing and shortness of breath may be present at different stages of lung cancer \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. It is still not clear whether these symptoms are related to LUAD and PAH.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eClinical Patient Data Collection\u003c/h2\u003e \u003cp\u003eData were collected from patients who underwent surgery between 2018 and 2023 in my department. We measured the ratio of PA/A from their preoperative chest CT. The inclusion criteria were as follows:1.Patients with a pathological diagnosis of lung adenocarcinoma, with stage from I-IV;2.Patients with a pathological diagnosis of AIS;3. The pathological diagnosis was inflammatory nodules and (AAH);4.No history of smoking or alcohol consumption;5.No history of hypertension, diabetes, or other tumor history.A total of 421 patients were included in the study, with 226 patients in the LUAD group, 116 patients in the AIS group, and 79 patients in the Benign nodule group.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMeasurement of PA/A ratio\u003c/h3\u003e\n\u003cp\u003eThe PA/A ratio is measured through imaging using chest enhanced CT to determine the ratio of the diameter of the pulmonary artery (PA) to the diameter of the aorta (A). Normally, the diameter of the PA should be less than or equal to the diameter of the A, with a PA/A ratio typically\u0026thinsp;\u0026le;\u0026thinsp;1. If the PA/A ratio is greater than 1, it may indicate PAH \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eData Collection for Bioinformatics Analysis\u003c/h3\u003e\n\u003cp\u003eThe TCGA-LUAD database includes 584 samples with 58,385 gene expressions. In contrast, the GEO database, GSE140797, comprises 14 samples (7 pairs of lung adenocarcinoma and normal tissues) with 29,834 gene expressions. The VSMCPRG dataset was obtained through literature review and includes 356 genes, of which 338 were annotated via Gene Ontology, and 18 were identified through literature searches\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003ePathological Paraffin Sample Collection\u003c/h3\u003e\n\u003cp\u003eA total of 17 paraffin-embedded samples were collected and divided into three groups: 5 cases of LUAD, 5 cases of AIS, and 7 cases of Benign nodules. For each patient, one sample of the lung lesion tissue and one sample of the adjacent normal tissue were collected. These samples were subjected to immunohistochemical (IHC) staining for the COMP antigen. The staining intensity was categorized as follows: no positive staining (negative), light yellow staining (weak positive), brownish yellow staining (positive), and brown staining (strong positive) \u003csup\u003e[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eSerum Sample Collection\u003c/h3\u003e\n\u003cp\u003eA total of 65 serum samples were collected. The LUAD group included 25 samples from patients with stages I to IV. The AIS group and the the Benign nodule group each included 20 samples, totaling 40 samples.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEdU Cell Proliferation Assay\u003c/h2\u003e \u003cp\u003eEdU (5-ethynyl-2'-deoxyuridine) is a thymidine deoxynucleotide analog that can be incorporated into newly synthesized DNA during DNA replication. In this experiment, recombinant COMP protein was co-cultured with HPASMC.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDetection of COMP on Pulmonary Artery Vasoconstriction\u003c/h3\u003e\n\u003cp\u003eThis study verified the effect of COMP on pulmonary artery vasoconstriction through two sets of experiments using both rat and human pulmonary arteries. The DMT 620M myograph instrument was used to measure the changes in vascular contraction.\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003eTable 1 *Indicates statistical significance, with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003cp\u003e\u003cimg 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\" width=\"631\" height=\"522\"\u003e\u003c/p\u003e \u003cp\u003eFrom the Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, we observed significant differences in patient age, with most patients over 60 years old concentrated in the LUAD group.Regarding gender, the proportion of females was significantly higher, consistent with previous reports showing that females have the highest incidence of lung adenocarcinoma \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. For PA/A values\u0026thinsp;\u0026ge;\u0026thinsp;1, the LUAD group had significantly higher PA/A values\u0026thinsp;\u0026ge;\u0026thinsp;1 compared to the AIS group and the Benign nodule group, with statistically significant differences.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eBioinformatics Data Analysis\u003c/h2\u003e \u003cp\u003eThe TCGA-LUAD (1198 genes), GSE140797 (269 genes), and VSMCPRG (356 genes) gene sets were all plotted as Venny diagrams using the Venny 2.1 network tool. Six differentially expressed genes were identified:MDK, COL1A1, COL3A1, PITX2, SIX1, and COMP.Subsequently, we performed pathway enrichment analysis on these six differential genes and created a bubble plot.After reviewing relevant literature \u003csup\u003e[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, we found that the (GO:0030199) was the most relevant to our study. The genes involved in this pathway include COL1A1, COMP, and COL3A1.Given the roles of these genes in maintaining vascular contractile phenotype and their effects on collagen proteins, we hypothesized that COMP might be a key gene involved in the PAH associated with LUAD \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eUsing the gene search function on the GEPIA platform, The results showed that COMP is widely distributed in the lungs, bile ducts, bones, and blood vessels. In disease states, COMP expression was significantly higher in lung adenocarcinoma, cholangiocarcinoma, breast cancer, and aortic diseases compared to normal tissues. Subsequently, we performed survival prognosis analysis of COMP and the results indicated no statistically significant difference between the high-expressing and low-expressing groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePathological Paraffin-embedded Samples Data Analysis\u003c/h2\u003e \u003cp\u003eThe mean value for the LUAD group (5.94\u0026thinsp;\u0026plusmn;\u0026thinsp;2.03) is significantly greater than both the AIS group (2.62\u0026thinsp;\u0026plusmn;\u0026thinsp;1.36) and the Benign nodule group (1.89\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12) after statistical analysis, and the difference between AIS and Benign nodule group is not statistically significant. This indicates that the expression of COMP in the extracellular matrix of the LUAD group is significantly higher than in both AIS group and Benign nodule group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFiguer 2 Fig A represents the Benign Nodule Group: ECM of the affected nodules showed no significant positive staining;Fig B represents the AIS Group:The staining of the ECM around the affected nodules was deeper compared to the Benign nodule group, and partial brownish staining was observed;Fig C represents the LUAD Group: A significant increase in brownish staining (positive). The expression of COMP was upregulated around the affected nodules,the pulmonary artery smooth muscle cells exhibited proliferation and thickening.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eThe Results of COMP in Serum Sample\u003c/h2\u003e \u003cp\u003eThe serum samples collected for this study totalled 65 cases.The OD values of each well were measured using an ELISA at a wavelength of 450 nm.\u003c/p\u003e \u003cp\u003eTable 2. The OD values measured by COMP .\u003c/p\u003e\u003cp\u003e\u003cimg 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\" width=\"724\" height=\"190\"\u003e\u003c/p\u003e\u003cp\u003eThe study included 25 samples of LUAD group with an average OD value of 0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28, 20 samples of AIS group with an average OD value of 0.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11, and 20 samples of the Benign nodule group with an average OD value of 0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12. Furthermore, within the LUAD group, the measured OD values were higher for more advanced stages. Specifically, the highest OD values (1.259 and 1.015) were observed in IV and III stage samples, respectively, while OD values for II and I stage lung adenocarcinoma samples were predominantly between 0.2 and 0.7. In contrast, the OD values for AIS samples were primarily between 0.1 and 0.3. For the Benign nodule group, the OD values were mainly between 0.1 and 0.2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eThe Effect of COMP on Proliferation of HPASMC\u003c/h2\u003e \u003cp\u003eIn this experiment, recombinant COMP protein was co-cultured with HPASMC. The mean value for the experimental groups was 37.50\u0026thinsp;\u0026plusmn;\u0026thinsp;10.303, while that for the control groups was 26.58\u0026thinsp;\u0026plusmn;\u0026thinsp;9.464. The experimental groups showed significantly higher cell proliferation compared to the control groups. This suggests that the HPASMC in the experimental groups exhibited significantly higher proliferation when co-cultured with recombinant COMP protein compared to the control groups. Additionally, multiple experimental and control groups were compared using EdU cell proliferation fluorescence imaging, which clearly demonstrated a higher number of proliferating cells in the experimental groups compared to the control groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eThe Role of COMP in the Contraction Function of Pulmonary Arteries\u003c/h2\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003eDetection of Contraction Function in Rat Pulmonary Arteries\u003c/h2\u003e \u003cp\u003eAfter isolating and standardizing the rat pulmonary arteries, they were treated with recombinant COMP protein. The experimental group was incubated with 25 ng/ml recombinant COMP protein for 1 hour, while the control group was not treated with recombinant COMP protein. Subsequently, the contraction function of the arteries was measured under the influence of various concentrations of norepinephrine (NE), acetylcholine (Ach), and endothelin-1 (ET-1). The comparison of contraction force values is based on the average values of the measured data.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eResults and Analysis(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003eFigure A: The cells were incubated for 1 hour, followed by the addition of 10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e mol/L PE to induce initial vasoconstriction, serving as a reference point. Subsequently, the contractile force was measured at Ach concentrations ranging from 10\u003csup\u003e\u0026minus;\u0026thinsp;9\u003c/sup\u003e to 10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e mol/L. The data points in Figure A represent the percentage of the baseline contractile force. As shown in Figure A, both the experimental and control groups exhibited a gradual decrease in contractile force with increasing Ach concentration. However, the decline in the experimental group was more gradual compared to the control group.\u003c/p\u003e \u003cp\u003eFigure B: The contractile force of the experimental group was compared to that of the control group under the action of PE. The linear graph in Figure B indicates that COMP has a weaker effect on vasoconstriction in pulmonary arteries compared to the control group.\u003c/p\u003e \u003cp\u003eFigure C: In the group treated with both COMP and ET-1, the contractile force was significantly higher than that of the control group when the ET-1 concentration reached 10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e mol/L. Statistical analysis revealed that the difference between the two groups was significant when the ET-1 concentration reached 10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e mol/L (COMP group: 119.70% \u0026gt; control group: 96.35%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eDetection of Contraction Function in Human Pulmonary Arteries\u003c/h2\u003e \u003cp\u003eIn this study, lung tissue samples were obtained from enrolled patients undergoing lobectomy. A total of 10 patient-derived lobar specimens were included in the experiments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eDrug Incubation Protocol\u003c/h2\u003e \u003cp\u003eTo minimize inter-individual variability, vessels from the same patient were used as self-controlled pairs, divided into experimental and control groups. The experimental group was incubated with recombinant COMP protein (25 ng/mL) for 1 hour, while the control group received no COMP treatment.In preliminary tests, human pulmonary arteries exhibited low sensitivity to PE stimulation, precluding reliable quantification of contractile responses. Consequently, ACh incubation was omitted in subsequent experiments.Finally, contractile responses of both groups were measured across a gradient of ET-1 concentrations to evaluate concentration-dependent effects.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAnalysis revealed that COMP-treated vessels exhibited significantly greater contractile responses to ET-1 compared to control vessels. This enhancement became particularly pronounced at an ET-1 concentration of 10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e mol/L(132.71% of baseline vs 72.84% in controls, p\u0026thinsp;=\u0026thinsp;0.0024).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn healthy individuals, the serum and synovial fluid COMP levels are approximately 5.93\u0026thinsp;\u0026plusmn;\u0026thinsp;1.95 \u0026micro;g/mL and 33\u0026thinsp;\u0026plusmn;\u0026thinsp;10 \u0026micro;g/mL \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Recent studies have revealed that COMP plays a critical role in the pathogenesis of various diseases, including malignancies, cardiovascular disorders, and fibrotic conditions \u003csup\u003e[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.Elevated COMP expression has been consistently observed in patients with hepatocellular carcinoma, colorectal cancer, and breast cancer. Additionally, emerging evidence suggests its involvement in prostate cancer, ovarian cancer, and thyroid malignancies \u003csup\u003e[\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Furthermore, COMP plays a significant role in vascular pathologies, including disorders of the pulmonary artery and aorta.\u003c/p\u003e \u003cp\u003ePA/A ratio measurement revealed that 53 patients in the LUAD group, 13 in the AIS group, and 8 with the Benign nodules group had a PA/A ratio\u0026thinsp;\u0026ge;\u0026thinsp;1, Statistical analysis demonstrated a significant difference (p\u0026thinsp;=\u0026thinsp;0.003), indicating that LUAD had a greater impact on pulmonary hypertension compared to AIS and the Benign nodules. In this study, the PA/A ratio was selected as a radiographic indicator for potential pulmonary hypertension based on the following rationale: First, existing literature suggests that the PA/A ratio is a more reliable non-invasive marker for pulmonary hypertension than the PA diameter alone, as it better correlates with reduced one-year median overall survival \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Second, the PA/A ratio accounts for individual variations in ascending aortic diameter, thereby minimizing potential confounding factors.\u003c/p\u003e \u003cp\u003eWe analyzed gene expression profiles from TCGA and GEO, along with a manually curated dataset of VSMCPRG derived from literature mining. Through this approach, COMP emerged as the most relevant candidate for further investigation.Using the GEPIA platform, we first validated the differential expression of COMP between LUAD tissues and normal controls. Our results demonstrated significant upregulation of COMP in LUAD tissues. Intriguingly, COMP was also markedly elevated in vascular disease samples compared to healthy controls, suggesting its potential influence on pulmonary vascular contractile phenotypes. Furthermore, we evaluated the prognostic value of COMP with LUAD patients. The results showed that there was no statistically significant difference between the high COMP expression group and the low COMP expression group (P\u0026thinsp;=\u0026thinsp;0.54). This might be because patients with early to mid-stage LUAD, after undergoing comprehensive treatments such as surgery, have removed the causes of the cancer and thus have no significant difference in survival prognosis.This observation suggests that LUAD-associated PAH symptoms\u0026mdash;such as chest tightness and exertional dyspnea\u0026mdash;could be alleviated or masked after standard oncologic treatment.\u003c/p\u003e \u003cp\u003eOur study on COMP expression in paraffin-embedded pathological specimens revealed that: Within the extracellular matrix of perinodular pulmonary arteries, COMP expression was significantly higher in the LUAD group compared to both the AIS group and the Benign nodule group, suggesting a potential pathological role in malignant progression.Further analysis demonstrated no significant difference in the Area% values among the three groups in the adjacent peri-nodular tissue, indicating that COMP expression levels in histologically normal tissue were not markedly elevated.These findings indicate that COMP expression exhibits significant variation across different pathological states. Its elevated expression in LUAD tissue appears to be closely associated with the formation and progression of the tumor microenvironment.\u003c/p\u003e \u003cp\u003eCOMP is an exocrine protein that can be measured in serum samples to determine its expression levels. Statistical analysis revealed significant differences in OD values between the LUAD group and both AIS group and the Benign nodule group. However, no significant statistical difference was observed between AIS group and the Benign nodule group. These findings indicate that the OD values in the LUAD group are significantly higher than those in AIS group and the Benign nodule group. Moreover, the OD value may increase as the tumor stage progresses. However, this result requires more data to be confirmed.\u003c/p\u003e \u003cp\u003eThe EdU cell proliferation assay demonstrated that COMP promotes the proliferation of HPASMC.Possible mechanisms include: COMP may regulate the expression of cell cycle-related proteins, promoting cells to transition from the G1 phase to the S phase, thereby increasing cell proliferation.COMP may inhibit apoptosis, thereby increasing cell survival rates and promoting cell proliferation.COMP may modulate the composition and structure of the ECM, providing a more favorable microenvironment for cell proliferation. This may also promote the secretion and deposition of ECM by vascular smooth muscle cells, enhancing ECM stability.COMP may promote the proliferation and migration of vascular smooth muscle cells, facilitating vascular remodeling. This is beneficial for vascular growth and repair under physiological conditions but can lead to abnormal vascular remodeling under pathological conditions.Under the stimulation of lung adenocarcinoma cells, COMP levels may increase, leading to enhanced proliferation of HPASMC.\u003c/p\u003e \u003cp\u003eIn our preliminary studies and literature review, we found that COMP is closely related to the maintenance of the contractile phenotype of blood vessels \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Therefore, if COMP can continue to exert a contractile effect on pulmonary arteries when its expression in the extracellular matrix increases, it would further support its positive role in PAH.\u003c/p\u003e \u003cp\u003eWe conducted the experiments in animals using rats as the model. PE (10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003emol/L) was added to stimulate the contraction of the pulmonary arteries, serving as the baseline. Next, we added various concentrations of ACh (from 10\u003csup\u003e\u0026minus;\u0026thinsp;9\u003c/sup\u003e to 10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e mol/L) to observe changes in the contraction force of the pulmonary arteries. Under the action of ACh, the contraction force of the experimental group was higher than that of the control group. However, the difference in contraction force between the two groups was not statistically significant according to the statistical analysis.\u003c/p\u003e \u003cp\u003eThe results of ET-1 showed that the contraction force of the experimental group gradually exceeded that of the control group when the ET-1 concentration reached 10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e mol/L. Statistical analysis revealed that the difference between the two groups was significant when the ET-1 concentration reached 10\u003csup\u003e\u0026minus;\u0026thinsp;7\u003c/sup\u003e mol/L (COMP group: 119.70% \u0026gt; control group: 96.35%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). We analyzed that under the influence of ACh, the contraction force of the pulmonary arteries in the COMP group decreased more slowly, indicating that COMP can exert a contractile effect on the pulmonary arteries. Regarding the addition of PE, there was no significant difference in the contraction force between the COMP group and the control group. This may be due to the relatively low concentrations of PE and COMP, which may not have been sufficient to produce a detectable difference in this concentration range. Additionally, PE primarily causes vasoconstriction by selectively activating α-adrenergic receptors, thereby enhancing smooth muscle contraction and increasing vascular resistance and blood pressure. ET-1, on the other hand, increases intracellular calcium ion concentrations by activating ET receptors, leading to smooth muscle contraction\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.From this perspective, COMP may share similar mechanisms in causing pulmonary artery contraction with ET-1, which could explain the more pronounced synergistic effect observed in their combined presence.\u003c/p\u003e \u003cp\u003eWe further tested the effect of COMP on human pulmonary arteries by using human tissue samples. The experimental results showed that under the same concentration of ET-1 stimulation, the contraction force of human pulmonary arteries treated with COMP was significantly higher than that of the control group.\u003c/p\u003e \u003cp\u003eIn summary, during the development of lung adenocarcinoma, cancer cells stimulate a significant increase in the expression of COMP in the extracellular matrix. COMP further promotes the occurrence of pulmonary hypertension by influencing the proliferation of pulmonary artery vascular smooth muscle cells and enhancing the contraction of pulmonary arteries. Most patients with lung adenocarcinoma may not experience symptoms related to pulmonary hypertension, which may be related to the early stage of cancer or the insufficient attention of clinical doctors. However, during the development of lung adenocarcinoma, the pulmonary artery vessels may already have undergone corresponding pathological and physiological changes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest Statement\u003c/h2\u003e \u003cp\u003eALL authors disclosed no relevant relationships.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthical Statement\u003c/h2\u003e \u003cp\u003e This research has been approved by the ethics committee of our hospital. The name of the ethics committee and institutional review board is the Medical Ethics Committee of the Seventh Affiliated Hospital of Sun Yat-sen University (Shenzhen), and the IRB number is KY-2025-427-01. I confirm that we have obtained the written informed consent from all participants.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eFunding Declaration\u003c/p\u003e \u003cp\u003eThere was no Funding in our research.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eD.Y., B.H.,S.J., J.Z.,Y.L. participated in research design. D.Y., B.H., Y.L. participated in the writing of the paper. D.Y., B.H. participated in the performance of the research. D.Y., B.H.,S.J., J.Z.,Y.L. contributed analytic tools or methods. D.Y., B.H.,S.J., J.Z.,Y.L.participated in data analysis.The authors declare no conflicts of interest and received no funding for this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data underlying this article are available in the article and in its online supplementary material.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSharman Moser S, Yaari S, Apter L, Poellinger B, Rheenen M, Arunachalam A, Chodick G, Hoshen M, Gazit S, Siegelmann-Danieli N. Mapping the patient journey and treatment patterns in early-stage (stage I-III) non-small cell lung cancer. Cancer Epidemiol. 2024;93:102678.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHouse KW. Personalized targeted therapy for lung cancer[J]. 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PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin Cancer Biol. 2019;59:125\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen DD, Hu WP, Xie L, Xiang GL, Wu QH, Qu JM, Li SQ, Guan LH, Liu D. Serum cartilage oligomeric matrix protein is decreased in patients with pulmonary hypertension: A potential protective factor. Pulm Circ. 2021;11:0271678X20978861.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchulz JN, Plomann M, Sengle G, Gullberg D, Krieg T, Eckes B. New developments on skin fibrosis\u0026mdash;Essential signals emanating from the extracellular matrix for the control of myofibroblasts. Matrix Biol. 2018, 68\u0026ndash;9, 522\u0026ndash;532.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnglund E, Canesin G, Papadakos KS, Vishnu N, Persson E, Reitsma B, Anand A, Jacobsson L, Helczynski L, Mulder H, et al. 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COPDGene Investigators; ECLIPSE Study Investigators. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med. 2012;367(10):913\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang L, Zheng J, Du Y, Huang Y, Li J, Liu B, Liu CJ, Zhu Y, Gao Y, Xu Q, Kong W, Wang X. Cartilage oligomeric matrix protein maintains the contractile phenotype of vascular smooth muscle cells by interacting with alpha(7)beta(1) integrin. Circ Res. 2010;106(3):514\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBloom JE, Chan W, Kaye DM, Stub D. State of Shock: Contemporary Vasopressor and Inotrope Use in Cardiogenic Shock. J Am Heart Assoc. 2023;12(15):e029787.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COMP, LUAD, PAH, PA/A Ratio, Bioinformatics","lastPublishedDoi":"10.21203/rs.3.rs-7848534/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7848534/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003ePulmonary arterial hypertension (PAH) associated with lung adenocarcinoma(LUAD) is a pathological state that emerges during LUAD progression. Cartilage oligomeric matrix protein (COMP) is an important extracellular matrix (ECM) glycoprotein and may be an independent prognostic biomarker.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe collected chest enhanced CT scans from clinical LUAD patients, screen PAH based on the PA/A ratio. By analyzing the TCGA-LUAD, GSE140797 and VSMCPRG gene sets, we identified the gene sets related to PAH in LUAD.Additional, we analysis of pathological samples, serum samples, EdU cell proliferation assays, and measurements of pulmonary artery vascular contraction functions.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e421 clinical patients were enrolled in this study.In the LUAD group ,the PA/A ratio\u0026thinsp;\u0026ge;\u0026thinsp;1 is significantly higher compared to both the Adenocarcinoma In Situ(AIS) group and the Benign nodule group.17 pathological samples revealed a significant upregulation of COMP in LUAD group compared to normal lung tissue.Serum samples showed significantly higher optical density (OD) values in the LUAD group compared to the other group.EdU experiment demonstrated that human pulmonary artery smooth muscle cells (HPASMC) co-cultured with COMP exhibited significantly higher proliferation rates compared to the control group.To assessing the effect of COMP on pulmonary artery vasculature, rat and human experiments indicated that the contraction force of the COMP group was significantly higher than that of the control group.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe findings suggest that LUAD patients may be associated with PAH, COMP may promote the development of PAH by enhancing the proliferation of pulmonary artery smooth muscle cells and the contractile function of pulmonary artery vessels.\u003c/p\u003e","manuscriptTitle":"Cartilage Oligomeric Matrix Protein in Pulmonary Arterial Hypertension Associated with Lung Adenocarcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 05:33:58","doi":"10.21203/rs.3.rs-7848534/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-03T21:35:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-02T00:19:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"236349788201947125287775514698561869431","date":"2026-01-19T01:20:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-06T17:16:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-16T03:24:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-16T03:23:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cardiothoracic Surgery","date":"2025-10-13T11:23:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4faa518-ddae-499b-9e1d-e926c45501ca","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-28T16:23:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 05:33:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7848534","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7848534","identity":"rs-7848534","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}