Integrative mRNA–miRNA Profiling of mTOR Pathway Dysregulation in High-Grade Serous Ovarian Carcinoma

Introduction & Background: High-grade serous ovarian carcinoma (HGSOC) is notorious for its poor prognosis owing to its inherent biological aggressiveness and development of chemoresistance. The mechanistic target of rapamycin (mTOR) pathway is dysregulated in 55% of epithelial ovarian cancer, representing an appealing therapeutic target. To date, the clinical trials of mTOR inhibitors have shown modest response. In this study, we investigate the mTOR pathway in a clinical cohort of primary, chemo-naive, high-grade ovarian cancer samples, along with its regulatory post-transcriptional miRNA regulation. Methodology: We performed differential gene expression analysis on 100 HGSOC patients from TCGA and 80 healthy controls (i.e., normal ovarian tissue) from GTEx. The differentially expressed genes (DEGs) were overlaid onto the KEGG mTOR signalling pathway, followed by functional enrichment analysis. Next, we conducted differential miRNA expression analysis on the same cohort and identified regulatory miRNA–mTOR gene pairs involved in cancer pathogenesis. Finally, we constructed an interaction network and identified key hub genes and miRNAs with potential prognostic significance. Results: We identified 95 mTOR pathway genes that were significantly differentially expressed, involving upstream regulators, core components, and downstream effectors. Functional pathway analysis revealed a prominent shift toward mTORC1 activation, accompanied by paradoxical activation of autophagy. The let-7 miRNA family was identified as a key regulator of the mTOR pathway, potentially facilitating disease progression. RICTOR downregulation, a key component of the mTORC2 complex, appears to play a critical role in this histotype. In addition, FNIP1, a tumour suppressor gene implicated in mTOR dysregulation, was found to correlate with survival outcomes. Conclusion: We propose a model of dual activation of mTORC1 and autophagy in HGSOC as the metabolic rewiring enabling cancer progression under nutrient and cellular stress.