Abstract
Ovarian cancer is a heterogeneous malignancy that poses tremendous clinical challenge. Based on unsupervised classification of whole-genome gene expression profiles, four molecular subtypes of ovarian cancer were recently identified. However, single-driver molecular events specific to these subtypes have not been clearly elucidated. We aim to characterize the regulatory mechanisms underlying the poor prognosis mesenchymal subtype of ovarian cancer using a systems biology approach, involving a variety of molecular modalities including gene and microRNA expression profiles. miR-508-3p emerged as the most powerful determinant that regulates a cascade of dysregulated genes in the mesenchymal subtype, including core genes involved in epithelial–mesenchymal transition (EMT) program. Moreover, miR-508-3p down-regulation, due to promoter hypermethylation, was directly correlated with metastatic behaviors in vitro and in vivo. Taken together, our multidimensional network analysis identified miR-508-3p as a master regulator that defines the mesenchymal subtype and provides a novel prognostic biomarker to improve management of this disease.
Highlights
Epithelial ovarian cancer ranks the top most deadly gynecologic cancer worldwide [1]
Transcriptomics profiling defines a heterogeneous subgroup of poor prognosis ovarian cancer
Using Bonome cohort (n = 182) as the training dataset [11], Konecny et al recapitulated the four molecular subtypes defined by The Cancer Genome Atlas (TCGA) dataset, of which the mesenchymal subtype was found to be significantly associated with poor survival [12] (Supplementary Fig. S1a)
Summary
Epithelial ovarian cancer ranks the top most deadly gynecologic cancer worldwide [1]. The majority of histological ovarian cancer types belong to high grade serous ovarian carcinoma (HGSOC), with relatively poor prognosis due to. Further exploration of the molecular mechanisms underlying ovarian cancer pathogenesis and progression are urgently in need. Ovarian cancer, until recently, has only been reflected by histopathological categorization and mutation status of major cancer genes [4]. Tothill et al employed unsupervised classification of gene expression patterns from 285 ovarian cancer patients, identifying four transcriptionally different ovarian cancer subtypes: immunoreactive, differentiated, proliferative, and Integrative network biology analysis identifies miR-508-3p as the determinant for the mesenchymal
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