TY - JOUR
T1 - Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer
AU - Dwivedi, Shailendra Kumar Dhar
AU - Mustafi, Soumyajit Banerjee
AU - Mangala, Lingegowda S.
AU - Jiang, Dahai
AU - Pradeep, Sunila
AU - Rodriguez-Aguayo, Cristian
AU - Ling, Hui
AU - Ivan, Cristina
AU - Mukherjee, Priyabrata
AU - Calin, George A.
AU - Lopez-Berestein, Gabriel
AU - Sood, Anil K.
AU - Bhattacharya, Resham
N1 - Funding Information:
This study was supported by the National Institutes of Health (NIH) CA 157481 to RB and the RGK Foundation and the Gilder Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2016/3/22
Y1 - 2016/3/22
N2 - 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.
AB - 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.
KW - BMI1
KW - Cisplatin sensitivity
KW - EMT
KW - MicroRNA
KW - Ovarian cancer
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U2 - 10.18632/oncotarget.7618
DO - 10.18632/oncotarget.7618
M3 - Article
AN - SCOPUS:84962911774
SN - 1949-2553
VL - 7
SP - 15093
EP - 15104
JO - Oncotarget
JF - Oncotarget
IS - 12
ER -