title: Emblica officinalis extract downregulates pro-angiogenic molecules via upregulation of cellular and exosomal miR-375 in human ovarian cancer cells.
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.
authors.affiliation: Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States.
authors.forename: Alok
authors.initials: A
authors.lastname: De
authors.affiliation: Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Powers
authors.affiliation: Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States.
authors.forename: Archana
authors.initials: A
authors.lastname: De
authors.affiliation: Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States.
authors.forename: Siddarth
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Veldhuizen
authors.affiliation: Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States.
authors.forename: Ajay
authors.initials: A
authors.lastname: Bansal
authors.affiliation: Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States.
authors.forename: Ramratan
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Kansas City VA Medical Center and Midwest Biomedical Research Foundation, Kansas City, MO 64128, United States.
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D055354:Exosomes / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D029842:Phyllanthus emblica / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics* / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C000597236:IGF1R protein, human; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D010936:Plant Extracts; D017451:Receptors, Somatomedin; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D017526:Receptor, IGF Type 1
keywords: Emblica officinalis; IGF1R; exosomes; microRNA-375; ovarian cancer