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

## TL;DR

This study explores how the mTOR pathway is dysregulated in high-grade serous ovarian cancer, identifying key genes and miRNAs that could lead to better targeted treatments.

## Contribution

The study reveals a dual activation of mTORC1 and autophagy in HGSOC, offering a new model for cancer progression and potential therapeutic targets.

## Key findings

- 95 mTOR pathway genes were significantly dysregulated in HGSOC patients.
- let-7 miRNAs were identified as key regulators facilitating mTOR pathway dysregulation.
- RICTOR downregulation and FNIP1 expression correlate with disease progression and survival outcomes.

## Abstract

High-grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer. It is often diagnosed at a late stage and eventually becomes resistant to standard chemotherapy. The mechanistic target of rapamycin (mTOR) is a key regulator of cellular functions including growth, survival, immune responses, and metabolism. To show how the mTOR pathway becomes dysregulated in HGSOC, we analysed gene expression data and microRNA patterns from both ovarian cancer patients and healthy individuals. We found that many of the genes involved in the mTOR pathway are unusually dysregulated. A group of regulatory molecules, the let-7 miRNAs, may allow this abnormal activity to continue. We also discovered a distinct pattern where one part of the pathway (mTORC1) is switched on while another (mTORC2) is switched off. These findings may help guide more effective, targeted treatments in the future targeting these pathways.

Introduction and 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 cancers, representing an appealing therapeutic target. To date, the clinical trials of mTOR inhibitors have shown modest response. In this study, we investigated 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. Conclusions: 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.