Integrative mRNA and miRNA Profiling Identifies Shared and Subtype-Associated PI3K-AKT-mTOR Pathway Dysregulation and...

Background: Endometriosis-associated ovarian cancers (EAOCs), including ovarian clear cell (OCCC) and endometrioid ovarian carcinoma (EnOC) subtypes, frequently exhibit transcriptomic dysregulation of the PI3K/AKT/mTOR signalling axis. While genomic aberrations are well-documented, the coordinated microRNA (miRNA)-mediated networks governing post-transcriptional remodelling of this pathway across these subtypes remain poorly defined. Methods: We conducted an integrative in silico meta-analysis of independent mRNA and small RNA sequencing datasets. The mRNA analysis included 120 EAOC samples, of which 68 were OCCC and 52 were EnOC, compared with 149 normal ovarian tissues. The miRNA analysis included 170 samples comprising 55 OCCC, 82 EnOC and 33 normal ovarian tissues. Differential expression analysis, dimensionality reduction (UMAP), functional enrichment, and topologically unweighted miRNA-mRNA interaction networks were evaluated. Results: Both subtypes showed significant transcriptomic dysregulation of the core pathway machinery, including PIK3CB and mTOR, while preserving mTORC2 components. Post-transcriptional concurrent downregulation of IRS1, GRB10, DDIT4, and PIK3CD, which were identified as candidate targets of the hub miRNAs hsa-miR-30a-5p, hsa-miR-30d-5p, and hsa-miR-7-5p, suggests further refined control of the pathway. The identification of highly connected hub genes linking mTOR, MAPK, and Wnt signalling pathways within the mTOR-regulatory network suggests that pathway modulation occurs through extensive crosstalk across multiple oncogenic signalling pathways in EAOCs. Conclusions: Transcriptomic dysregulation of the mTOR pathway in EAOCs reflects not only genomic alterations but also potential post-transcriptional regulation. Despite subtype-specific transcriptomic differences, both exhibited transcriptional upregulation of components of the canonical PI3K/AKT/mTOR signalling axis. Pathway modulation through the miRNA regulatory network exhibited potential crosstalk across oncogenic pathways and hub genes.