MicroRNA-29B (mir-29b) regulates the Warburg effect in ovarian cancer by targeting AKT2 and AKT3
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Yue Teng1,*, Yan Zhang2,*, Kai Qu3,*, Xinyuan Yang1, Jing Fu1, Wei Chen3, Xu Li2
1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
2Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
*These authors have contributed equally to this work
Xu Li, e-mail: [email protected]
Keywords: epithelial ovarian cancer, Warburg effect, microRNA, miR-29b, AKT
Received: April 11, 2015 Accepted: September 14, 2015 Published: October 20, 2015
Epithelial ovarian cancer (EOC) is the most lethal and aggressive gynecological malignancy, and abnormal cellular metabolism significantly contributes to cancer onset and progression. Here, we report that miR-29b negatively regulates AKT2/AKT3 expression, causing HK2/PKM2 downregulation and leading to a decreased Warburg effect and slowed ovarian cancer progression. Compared to normal ovaries, ovaries with epithelial cancer exhibited lower miR-29b expression at both cellular/histological levels. Glucose consumption and lactate production experiments confirmed miR-29b's regulation of EOC metabolism. A luciferase reporter assay confirmed the direct binding of miR-29b to AKT2/AKT3 3′ UTRs. miR-29b silencing correlated with increased expression of AKT2/3, pAKT2/3, HK2, and PKM2. Pyruvic acid and NAD+/NADH levels also changed when miR-29b expression was suppressed; this effect could be blocked by specific AKT inhibitors, suggesting the miR-29b-AKT axis regulates the Warburg effect in ovarian cancer. In xenograft mouse models, miR-29b inhibited tumor formation in vivo. In vivo imaging also demonstrated that miR-29b agomir inhibited the relative uptake of 18F-FDG in the xenograft tumors, suggesting that miR-29b over-expression could negatively modulate tumor glucose metabolism in vivo. Taken together, our study suggests that miR-29b regulates the Warburg effect in EOC via AKT2/AKT3 and may provide novel options for future treatments for EOC.
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