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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>High-grade serous ovarian cancer (HGSOC) exhibits substantial molecular heterogeneity during disease progression. We investigated stage-specific changes in PI3K\u2013AKT-associated signaling programs from early tumorigenesis to metastatic disease. Two publicly available microarray datasets, GSE36668 (normal, borderline, and carcinoma; n = 4 per group) and GSE73064 (primary tumor, ascites, and metastasis; n = 5 per group), were analyzed using differential expression, gene set enrichment, protein\u2013protein interaction network analysis, and hub-gene identification. PI3K\u2013AKT-associated genes were subsequently characterized by functional enrichment, exploratory survival analysis using KM Plotter, and independent stage-stratified validation in TCGA-OV. Survival analyses were considered exploratory because KM Plotter-derived p-values were not adjusted for multiple testing. Carcinoma-associated genes were predominantly linked to extracellular matrix remodeling and receptor tyrosine kinase-mediated PI3K signaling. Ascites-associated genes were enriched in integrin-dependent signaling and microenvironmental adaptation, whereas metastasis-associated genes formed inflammatory and survival-related modules involving IL6, JAK1, PTK2, AREG, EIF4E, and HSP90B1. In stage-stratified TCGA-OV analysis, all seven metastasis-associated genes were significantly associated with overall survival in Stage IV disease, supporting the prognostic relevance of the metastatic module. HGSOC progression is characterized by stage-associated reorganization of PI3K\u2013AKT-related signaling rather than uniform pathway activation. The identified molecular programs suggest a transition from RTK-associated proliferative signaling in carcinoma to integrin-dependent survival adaptation in ascites and inflammatory survival signaling during metastasis.<\/jats:p>","DOI":"10.3390\/ijms27198700","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:09:25Z","timestamp":1790683765000},"page":"8700","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Stage-Specific Rewiring of PI3K\u2013AKT Signaling During Serous Ovarian Cancer Progression: An Integrated Transcriptomic and Network Analysis"],"prefix":"10.3390","volume":"27","author":[{"given":"Iman Jaafar","family":"Abdulrahman","sequence":"first","affiliation":[{"name":"Obstetrics and Gynecology Department, Akre Obstetrics and Gynecology Hospital, Duhok General Directorate of Health, Ministry of Health, Duhok 42001, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Sana Ismael","family":"Ameen","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Faculty of General Medicine, Koya University, Koya 44023, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8246-595X","authenticated-orcid":false,"given":"Hossein","family":"Azizi","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Cancer, College of Biotechnology, Amol University of Special Modern Technologies, Amol 49767, Iran"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4813-1213","authenticated-orcid":false,"given":"Thomas","family":"Skutella","sequence":"additional","affiliation":[{"name":"Institute for Anatomy and Cell Biology, Medical Faculty, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Liberto, J.M., Chen, S.-Y., Shih, I.-M., Wang, T.-H., Wang, T.-L., and Pisanic, T.R. 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