Oncotarget

Research Papers:

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 and Resham Bhattacharya` _

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Oncotarget. 2016; 7:15093-15104. https://doi.org/10.18632/oncotarget.7618

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Abstract

Shailendra Kumar Dhar Dwivedi1, Soumyajit Banerjee Mustafi1, Lingegowda S. Mangala4,6, Dahai Jiang4,6, Sunila Pradeep4, Cristian Rodriguez-Aguayo6,7, Hui Ling7, Cristina Ivan4, Priyabrata Mukherjee3, George A. Calin6,7, Gabriel Lopez-Berestein6,7, Anil K. Sood4,5,6, Resham Bhattacharya1,2

1Department of Obstetrics and Gynecology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

2Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA

3Department of Pathology, Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

4Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

5Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

6The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

7Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Resham Bhattacharya e-mail: [email protected]

Keywords: BMI1, microRNA, ovarian cancer, EMT, cisplatin sensitivity

Received: September 29, 2015     Accepted: January 23, 2016     Published: February 23, 2016

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.


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