Emblica officinalis extract downregulates pro-angiogenic molecules via upregulation of cellular and exosomal miR-375 in human ovarian cancer cells.

// Alok De 1 , Benjamin Powers 1 , Archana De 1 , Jianping Zhou 1 , Siddarth Sharma 1 , Peter Van Veldhuizen 1 , Ajay Bansal 1 , Ramratan Sharma 1 , Mukut Sharma 1 1 Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States Correspondence to: Alok De, email: Alok.De@va.gov , alokde2001@yahoo.com Keywords: ovarian cancer, Emblica officinalis, microRNA-375, IGF1R, exosomes Received: January 05, 2016     Accepted: March 31, 2016      Published: April 25, 2016 ABSTRACT 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.