MicroRNA-Regulated Ubiquitination and Lipid Metabolism Networks are Associated with Chemotherapy Response in Ovarian Cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is a highly lethal gynecologic cancer, in part due to resistance to platinum-based chemotherapy reported among 20% of patients. This study aims to characterize the biological mechanisms underlying chemotherapy resistance, which remain poorly understood.Analysis of mRNA/microRNA sequencing data from HGSOC patients of The Cancer Genome Atlas identified 196 differentially expressed mRNAs enriched for adaptive immunity and translation, and 21 differentially expressed microRNAs associated with angiogenesis. Co-expression network analysis identified two mRNA networks associated with chemotherapy response, which were enriched for ubiquitination and lipid metabolism, as well as three associated microRNA networks enriched for lipoprotein transport and oncogenic pathways. These network modules replicated in two independent ovarian cancer cohorts. Moreover, integrative analyses of the mRNA, microRNA and genomics (i.e. single nucleotide polymorphisms) datasets revealed potential regulation of the mRNA networks by the associated microRNAs and SNPs (i.e. expression quantitative trait loci).Thus, we report novel transcriptional networks and biological pathways associated with resistance to platinum-based chemotherapy among HGSOC patients. These results improve our understanding of the effector networks and regulators of chemotherapy response, which will help to elucidate novel therapeutic targets for ovarian cancer.