Integrative network biology analysis identifies miR-508-3p as the determinant for the mesenchymal identity and a strong prognostic biomarker of ovarian cancer

• Published in: Oncogene 2019-03, Vol.38 (13), p.2305-2319
• Main Authors: Zhao, Linjie, Wang, Wei, Xu, Lian, Yi, Tao, Zhao, Xia, Wei, Yuquan, Vermeulen, Louis, Goel, Ajay, Zhou, Shengtao, Wang, Xin
• Format: Article
• Language: English
• Subjects: 38/39; 631/67/1517/1709; 692/53/2422; Animals; Apoptosis; Biochemistry; Biomarkers; Biomarkers, Tumor - genetics; Cancer cells; Cancer metastasis; Carcinoma, Ovarian Epithelial - diagnosis; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - pathology; Care and treatment; Cell Biology; Cell Line, Tumor; Chemotherapy; Datasets as Topic; Epithelial-Mesenchymal Transition - genetics; Female; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Gene mutation; Gene Regulatory Networks; Genes; Genomes; Genomics; Genomics - methods; Human Genetics; Humans; Internal Medicine; Malignancy; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNA; MicroRNAs - physiology; miRNA; Novels; Oncology; Ovarian cancer; Ovarian Neoplasms - diagnosis; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Prognosis; Stem cells; Systems Biology - methods; Systems Integration; Transcriptome
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0577-5

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.