Network vulnerability‐based and knowledge‐guided identification of microRNA biomarkers indicating platinum resistance in high‐grade serous ovarian cancer
Open Access
- 29 October 2019
- journal article
- research article
- Published by Wiley in Clinical and Translational Medicine
- Vol. 8 (1), 1-11
- https://doi.org/10.1186/s40169-019-0245-6
Abstract
High-grade serous ovarian cancer (HGSC), the most common ovarian carcinoma type, is associated with the highest mortality rate among all gynecological malignancies. As chemoresistance has been demonstrated as the major challenge in improving the prognosis of HGSC patients, we here aimed to identify microRNA (miRNA) biomarkers for predicting platinum resistance and further explore their functions in HGSC. We developed and applied our network vulnerability-based and knowledge-guided bioinformatics model first time for the study of drug-resistance in cancer. Four miRNA biomarkers (miR-454-3p, miR-98-5p, miR-183-5p and miR-22-3p) were identified with potential in stratifying platinum-sensitive and platinum-resistant HGSC patients and predicting prognostic outcome. Among them, miR-454-3p and miR-183-5p were newly discovered to be closely implicated in platinum resistance in HGSC. Functional analyses highlighted crucial roles of the four miRNA biomarkers in platinum resistance through mediating transcriptional regulation, cell proliferation and apoptosis. Moreover, expression patterns of the miRNA biomarkers were validated in both platinum-sensitive and platinum-resistant ovarian cancer cells. With bioinformatics modeling and analysis, we identified and confirmed four novel putative miRNA biomarkers, miR-454-3p, miR-98-5p, miR-183-5p and miR-22-3p that could serve as indicators of resistance to platinum-based chemotherapy, thereby contributing to the improvement of chemotherapeutic efficiency and optimization of personalized treatments in HGSC.Keywords
Funding Information
- National Natural Science Foundation of China (31670851, 31600670)
- National Natural Science Foundation of China (31670851, 31600670, 31900490)
- Jiangsu Planned Projects for Postdoctoral Research Funds (2018K173C)
- China Postdoctoral Science Foundation (2019M651938)
This publication has 56 references indexed in Scilit:
- A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesisProceedings of the National Academy of Sciences of the United States of America, 2013
- Pancreatic cancer genomes reveal aberrations in axon guidance pathway genesNature, 2012
- Wnt/β-Catenin Signaling and DiseaseCell, 2012
- Involvement of microRNA‐93, a new regulator of PTEN/Akt signaling pathway, in regulation of chemotherapeutic drug cisplatin chemosensitivity in ovarian cancer cellsFEBS Letters, 2012
- Enrichment Map: A Network-Based Method for Gene-Set Enrichment Visualization and InterpretationPLOS ONE, 2010
- Cancer systems biology: a network modeling perspectiveCarcinogenesis: Integrative Cancer Research, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray ExperimentsStatistical Applications in Genetics and Molecular Biology, 2004
- Ovarian cancer: strategies for overcoming resistance to chemotherapyNature Reviews Cancer, 2003
- Ovarian cancer: progress and continuing controversies in managementEuropean Journal of Cancer, 2002