Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer

Shailendra Kumar Dhar Dwivedi, Soumyajit Banerjee Mustafi, Lingegowda S. Mangala, Dahai Jiang, Sunila Pradeep, Cristian Rodriguez-Aguayo, Hui Ling, Cristina Ivan, Priyabrata Mukherjee, George A. Calin, Gabriel Lopez-Berestein, Anil K. Sood, Resham Bhattacharya

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Treatment of chemo-resistant ovarian cancer (OvCa) remains clinically challenging and there is a pressing need to identify novel therapeutic strategies. Here we report that multiple mechanisms that promote OvCa progression and chemo-resistance could be inhibited by ectopic expression of miR-15a and miR-16. Significant correlations between low expression of miR-16, high expression of BMI1 and shortened overall survival (OS) were noted in high grade serous (HGS) OvCa patients upon analysis of The Cancer Genome Atlas (TCGA). Targeting BMI1, in vitro with either microRNA reduced clonal growth of OvCa cells. Additionally, epithelial to mesenchymal transition (EMT) as well as expression of the cisplatin transporter ATP7B were inhibited by miR-15a and miR-16 resulting in decreased degradation of the extra-cellular matrix and enhanced sensitization of OvCa cells to cisplatin. Nanoliposomal delivery of the miR-15a and miR-16 combination, in a pre-clinical chemo-resistant orthotopic mouse model of OvCa, demonstrated striking reduction in tumor burden compared to cisplatin alone. Thus, with the advent of miR replacement therapy some of which are in Phase 2 clinical trials, miR-15a and miR-16 represent novel ammunition in the anti-OvCa arsenal.

Original languageEnglish (US)
Pages (from-to)15093-15104
Number of pages12
JournalOncotarget
Volume7
Issue number12
DOIs
StatePublished - Mar 22 2016

Keywords

  • BMI1
  • Cisplatin sensitivity
  • EMT
  • MicroRNA
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology

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    Dwivedi, S. K. D., Mustafi, S. B., Mangala, L. S., Jiang, D., Pradeep, S., Rodriguez-Aguayo, C., Ling, H., Ivan, C., Mukherjee, P., Calin, G. A., Lopez-Berestein, G., Sood, A. K., & Bhattacharya, R. (2016). Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer. Oncotarget, 7(12), 15093-15104. https://doi.org/10.18632/oncotarget.7618