Emblica officinalis extract downregulates pro-angiogenic molecules via upregulation of cellular and exosomal miR-375 in human ovarian cancer cells
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Alok De1, Benjamin Powers1, Archana De1, Jianping Zhou1, Siddarth Sharma1, Peter Van Veldhuizen1, Ajay Bansal1, Ramratan Sharma1, Mukut Sharma1
1Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States
Alok De, email: [email protected], [email protected]
Keywords: ovarian cancer, Emblica officinalis, microRNA-375, IGF1R, exosomes
Received: January 05, 2016 Accepted: March 31, 2016 Published: April 25, 2016
Ovarian cancer (OC) is highly resistant to current treatment strategies based on a combination of surgery, chemotherapy and radiation therapy. We have recently demonstrated the anti-neoplastic effect of Amla extract (Emblica officinalis, AE) on OC cells in vitro and in vivo. We hypothesized that AE attenuates growth of OC through microRNA (miR)-regulated mechanism(s). The inhibitory effect of AE on proliferation, migration and invasiveness (P≤0.001) of SKOV3 cells and >90% attenuation of tumor growth in a xenograft mouse model suggested multiple targets. RT-qPCR analysis of microRNAs associated with OC showed a >2,000-fold increase in the expression of miR-375 in AE-treated SKOV3 cells that was blocked by an exogenous miR-375 inhibitor (P≤0.001). AE also decreased the gene and protein expression of IGF1R, a target of miR-375 (P≤0.001), and SNAIL1 (P≤0.002), an EMT-associated transcription factor that represses E-cadherin expression (P≤0.003). AE increased E-cadherin expression (P≤0.001). Treatment of SKOV3 cells with AE resulted in increased miR-375 in exosomes in the medium (P≤0.01). Finally, AE significantly decreased the expression of IGF1R and SNAIL1 proteins during attenuation of SKOV3-derived xenograft tumor. Together, these results show that AE modulates cancer cells and the tumor microenvironment via activation of miR-375 and by targeting IGF1R and SNAIL1 in OC cells.
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