Stage-Specific Rewiring of PI3K-AKT Signaling During Serous Ovarian Cancer Progression: An Integrated Transcriptomic and Network Analysis.
4 affiliations
- 1Obstetrics and Gynecology Department, Akre Obstetrics and Gynecology Hospital, Duhok General Directorate of Health, Ministry of Health, Duhok 42001, Kurdistan Region, Iraq.
- 2Department of Gynecology and Obstetrics, Faculty of General Medicine, Koya University, Koya 44023, Kurdistan Region, Iraq.
- 3Department of Stem Cells and Cancer, College of Biotechnology, Amol University of Special Modern Technologies, Amol 49767, Iran.
- 4Institute for Anatomy and Cell Biology, Medical Faculty, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
Abstract
High-grade serous ovarian cancer (HGSOC) exhibits substantial molecular heterogeneity during disease progression. We investigated stage-specific changes in PI3K-AKT-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-protein interaction network analysis, and hub-gene identification. PI3K-AKT-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-AKT-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.
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BibTeX
@article{abdulrahman2026stagespecific,
title = {{Stage-Specific Rewiring of PI3K-AKT Signaling During Serous Ovarian Cancer Progression: An Integrated Transcriptomic and Network Analysis.}},
author = {Iman Jaafar Abdulrahman and Sana Ismael Ameen and Hossein Azizi and Thomas Skutella},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198700},
url = {https://europepmc.org/article/MED/42883944},
note = {CC BY},
}
RIS
TY - JOUR
TI - Stage-Specific Rewiring of PI3K-AKT Signaling During Serous Ovarian Cancer Progression: An Integrated Transcriptomic and Network Analysis.
AU - Iman Jaafar Abdulrahman
AU - Sana Ismael Ameen
AU - Hossein Azizi
AU - Thomas Skutella
PY - 2026
DA - 2026/09/29
JO - International journal of molecular sciences
DO - 10.3390/ijms27198700
UR - https://europepmc.org/article/MED/42883944
AB - High-grade serous ovarian cancer (HGSOC) exhibits substantial molecular heterogeneity during disease progression. We investigated stage-specific changes in PI3K-AKT-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-protein interaction network analysis, and hub-gene identification. PI3K-AKT-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-AKT-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.
SN - 1422-0067
ER -