{"paper_id":"5ecf3ea6-e07f-4e21-81b4-8ffc9d599216","body_text":"Abstract\nBackground\nIn this study, we investigated the genes and pathways associated with the progression of endometriosis to ovarian cancer (OC).\nMaterials and Methods\nWe utilized the GenCLip3 and DisGeNET databases to identify genes related to OC and endometriosis. Protein–protein interaction analysis of the common genes was performed using the STRING database, and visualization was achieved through Cytoscape. The Cytohubba plugin of Cytoscape was employed to determine hub genes. Transcription factors (TFs) and microRNAs (miRNAs) targeting the hub genes were identified using the miRTarBase and ChEA databases, linked to the Enrichr software. Furthermore, we investigated and analyzed the hub genes associated with ovarian cancer risk using the Comparative Toxicogenomics Database.\nResults\nThrough the GenCLip3 and DisGeNET databases, we identified 311 genes shared between OC and endometriosis. Analysis of the protein–protein interaction network and hub gene identification revealed eight hub genes: STAT3, TP53, SRC, PIK3CA, JUN, CTNNB1, ESR1, and RELA. Among the miRNAs, hsa-miR-146a-5p exhibited the most interactions with the hub genes, while RELA showed the highest number of interactions among the TFs. Finally, our findings demonstrated that TP53, RELA, IL-6, and STAT3 exhibited the strongest correlations with ovarian cancer, as indicated by their high scores.\nConclusion\nIn conclusion, the hub genes identified in this study are involved in the progression of endometriosis to OC. Understanding the associated upstream and downstream pathways can aid in the development of targeted treatment strategies and improve the survival outcomes for patients.\nSimilar content being viewed by others\nData Availability\nThis is a review study, and it is not an original. Data availability is corresponding author responsibility.\nReferences\nHorne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022;379:e070750.\nSignorile PG, Viceconte R, Baldi A. New insights in pathogenesis of endometriosis. Front Med. 2022;9: 879015.\nNijkang NP, Anderson L, Markham R, Manconi F. Endometrial polyps: Pathogenesis, sequelae and treatment. SAGE Open Med. 2019;7:2050312119848247.\nBabadi AJ, Kouti RN, Zeinali M, Lordejani MA, Marandi HJ, Farhadi E. Effect of Cervical Index changes on cervical pain. J Iran Med Counc. 2024.\nCasalechi M, Tripodi A, Reis FM, Carullo G, Mondini I, Di Stefano G, et al. The link between inflammation and hemostasis in endometriosis: a call for research. J Endometr Uterine Disorders. 2023;3: 100040.\nHerreros-Villanueva M, Chen C-C, Tsai E-M, Er T-K. Endometriosis-associated ovarian cancer: What have we learned so far? Clin Chim Acta. 2019;493:63–72.\nSo KA, Hong SR, Kim NR, Yang EJ, Shim S-H, Lee SJ, et al. Association between atypical endometriosis and ovarian malignancies in the real world. J Ovarian Res. 2021;14(1):110.\nLee HJ, Lee B, Choi H, Kim T, Kim Y, Kim YB. Impact of hormone replacement therapy on risk of ovarian cancer in postmenopausal women with de novo endometriosis or a history of endometriosis. Cancers (Basel). 2023;15(6):1708.\nMurakami K, Kotani Y, Nakai H, Matsumura N. Endometriosis-associated ovarian cancer: the origin and targeted therapy. Cancers. 2020;12(6):1676.\nYachida N, Yoshihara K, Yamaguchi M, Suda K, Tamura R, Enomoto T. How does endometriosis lead to ovarian cancer? The molecular mechanism of endometriosis-associated ovarian cancer development. Cancers. 2021;13(6):1439.\nAbdulwahid A-HRR, Mahdi MH, Amiri BS, Koosehlar E, Kazemi N, Ghiasi F, et al. In silico analysis of genes and molecular pathways involved in the pathogenesis of follicular lymphoma. Iran J Pediatric Hematol Oncol. 2024.\nTeng YH, Liu FC, Huang SY, Kuo CF, Yu HP. Epidemiology and mortality of ovarian cancer in Taiwan: a population-based study. J Clin Med. 2022;11(19):5627.\nWang W, Cho U, Yoo A, Jung C-L, Kim B, Kim H, et al. Wnt/β-Catenin inhibition by CWP232291 as a novel therapeutic strategy in ovarian cancer. Front Oncol. 2022;12: 852260.\nLaganà AS, Garzon S, Götte M, Viganò P, Franchi M, Ghezzi F, et al. The pathogenesis of endometriosis: molecular and cell biology insights. Int J Mol Sci. 2019;20(22):5615.\nKabacaoglu D, Ruess DA, Ai J, Algül H. NF-κB/Rel transcription factors in pancreatic cancer: focusing on RelA, c-Rel, and RelB. Cancers. 2019;11(7):937.\nJinawath N, Vasoontara C, Jinawath A, Fang X, Zhao K, Yap K-L, et al. Oncoproteomic analysis reveals co-upregulation of RELA and STAT5 in carboplatin resistant ovarian carcinoma. PLoS ONE. 2010;5(6): e11198.\nAsghari S, Valizadeh Dizajeykan A, Ahmadi M, Barzegari A, Rikhtegar R, Dolati S, et al. Evaluation of ovarian cancer risk in granulosa cells treated with steroid-depleted endometriosis serum: Role of NF-κB/RelA and AKT. J Cell Physiol. 2019;234(7):12011–8.\nMarla S, Mortlock S, Houshdaran S, Fung J, McKinnon B, Holdsworth-Carson S, et al. Genetic risk factors for endometriosis near estrogen receptor 1 and coexpression of genes in this region in endometrium. Mol Hum Reprod. 2021;27(1):gaaa082.\nLiu Y, Wang J, Zhang X. An update on the multifaceted role of NF-kappaB in endometriosis. Int J Biol Sci. 2022;18(11):4400.\nEmami M, Shafie D, Vakhshoori M, Eghbali-Babadi M, Ahmadipour E, Khosravi A. Evaluation of the efficiency of indirect blood pressure measurement methods in comparison to intra-arterial reading among Iranian individuals. Int Cardiovasc Res J. 2020;14(3).\nAléssio AM, Höehr NF, Siqueira LH, Ozelo MC, de Pádua MA, Annichino-Bizzacchi JM. Association between estrogen receptor alpha and beta gene polymorphisms and deep vein thrombosis. Thromb Res. 2007;120(5):639–45.\nYu X, Zhao QY, Yaman M, Emly SM, Lee JK, Su H, et al. Hormone-induced thrombosis is mediated through non-canonical fibrin(ogen) aggregation and a novel estrogen target in zebrafish. bioRxiv. 2024:2024.11.13.623199.\nGuo T, Dong X, Xie S, Zhang L, Zeng P, Zhang L. Cellular mechanism of gene mutations and potential therapeutic targets in ovarian cancer. Cancer Manag Res. 2021;2021:3081–100.\nGhoneum A, Abdulfattah AY, Said N. Targeting the PI3K/AKT/mTOR/NFκB axis in ovarian cancer. J Cellul Immunol. 2020;2(2):68.\nWu M, Zhang Y. MiR-182 inhibits proliferation, migration, invasion and inflammation of endometrial stromal cells through deactivation of NF-κB signaling pathway in endometriosis. Mol Cell Biochem. 2021;476:1575–88.\nQiu L, Wang J, Chen M, Chen F, Tu W. Exosomal microRNA-146a derived from mesenchymal stem cells increases the sensitivity of ovarian cancer cells to docetaxel and taxane via a LAMC2-mediated PI3K/Akt axis. Int J Mol Med. 2020;46(2):609–20.\nBischof K, Knappskog S, Hjelle SM, Stefansson I, Woie K, Salvesen HB, et al. Influence of p53 isoform expression on survival in high-grade serous ovarian cancers. Sci Rep. 2019;9(1):5244.\nHuang H, Chen AY, Ye X, Guan R, Rankin GO, Chen YC. Galangin, a flavonoid from lesser galangal, induced apoptosis via p53-dependent pathway in ovarian cancer cells. Molecules. 2020;25(7):1579.\nNguyen VHL, Hough R, Bernaudo S, Peng C. Wnt/β-catenin signalling in ovarian cancer: Insights into its hyperactivation and function in tumorigenesis. J Ovarian Res. 2019;12:1–17.\nIshizaka A, Taguchi A, Tsuruga T, Maruyama M, Kawata A, Miyamoto Y, et al. Endometrial cancer with concomitant endometriosis is highly associated with ovarian endometrioid carcinoma: a retrospective cohort study. BMC Womens Health. 2022;22(1):332.\nWang X, Zhang J, Liu X, Wei B, Zhan L. Long noncoding RNAs in endometriosis: biological functions, expressions, and mechanisms. J Cell Physiol. 2021;236(1):6–14.\nRad HF, Karimi MS, Behfar M, Nazari A, Hassani N, Hasanvand A, et al. LncRNA Linc00261 sponge’s miR-33-regulated PI3-kinase in autism disorder. Gene Reports. 2025;38: 102115.\nHan O, Alci A, Yildirim HT, Gokkaya M, Yalcin N, Kandemir S, et al. β-catenin expression in endometrioid type endometrial cancer: expression patterns and impact on disease outcomes. Oncol Lett. 2024;28(6):580.\nWang Y, Nie X-B, Liu S-J, Liu J, Bian W-H. Curcumol attenuates endometriosis by inhibiting the JAK2/STAT3 signaling pathway. Med Sci Monitor Int Med J Exp Clin Res. 2022;28:e934914–21.\nAdereh A, Amini P, Fateh A, Faghihkhorasani F, Khdakarim N, Marashi SM, et al. Loc646329 sponges miR-21 to reduce RAS/MAP kinase signaling pathway in oral squamous cell carcinoma (OSCC). Naunyn-Schmiedeberg's Arch Pharmacol. 2024:1–9.\nLiang R, Chen X, Chen L, Wan F, Chen K, Sun Y, et al. STAT3 signaling in ovarian cancer: a potential therapeutic target. J Cancer. 2020;11(4):837.\nWu C-J, Sundararajan V, Sheu B-C, Huang RY-J, Wei L-H. Activation of STAT3 and STAT5 signaling in epithelial ovarian cancer progression: mechanism and therapeutic opportunity. Cancers. 2019;12(1):24.\nYazdi M, Alaee M, Ahadi S, Khanicherag P, Ghayem E, Babadi GFG, et al. Therapeutic potential of alpha-pinene in breast cancer: targeting miR-21 and PTEN gene expression: alpha-pinene in breast cancer: targeting miR-21 and PTEN. Galen Med J. 2024;13:e3613-e.\nBora G, Yaba A. The role of mitogen-activated protein kinase signaling pathway in endometriosis. J Obstetr Gynaecol Res. 2021;47(5):1610–23.\nDou Y, Jiang X, Xie H, He J, Xiao S. The Jun N-terminal kinases signaling pathway plays a “seesaw” role in ovarian carcinoma: a molecular aspect. J Ovar Res. 2019;12:1–11.\nSimatou A, Simatos G, Goulielmaki M, Spandidos DA, Baliou S, Zoumpourlis V. Historical retrospective of the SRC oncogene and new perspectives. Mol Clin Oncol. 2020;13(4):21.\nWang Y, Luo X, Wu N, Liao Q, Wang J. SRC-3/TRAF4 facilitates ovarian cancer development by activating the PI3K/AKT signaling pathway. Med Oncol. 2023;40(2):76.\nAcknowledgements\nThe authors appreciate and thank the efforts of the Center for the Development of Clinical Researches of the Educational and Therapeutic Research Complex of Birjand University of Medical Science.\nFunding\nNone.\nAuthor information\nAuthors and Affiliations\nCorresponding authors\nEthics declarations\nConflict of interest\nThe authors declare that they have no conflict of interest.\nEthical Approval\nThis article does not contain any studies with human participants or animals performed by any of the authors.\nConsent for Publication\nNot applicable.\nAdditional information\nPublisher's Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nSupplementary Information\nBelow is the link to the electronic supplementary material.\nRights and permissions\nSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.\nAbout this article\nCite this article\nZarifi, N., Fateh, A., Fazeli, R. et al. Evaluation of Genes and Molecular Pathways Involved in the Switch of Endometriosis to Ovarian Cancer: A Systems Biology Approach. Indian J Gynecol Oncolog 23, 78 (2025). https://doi.org/10.1007/s40944-025-01010-3\nReceived:\nRevised:\nAccepted:\nPublished:\nVersion of record:\nDOI: https://doi.org/10.1007/s40944-025-01010-3","source_license":"CC0","license_restricted":false}