title: MicroRNA-29B (mir-29b) regulates the Warburg effect in ovarian cancer by targeting AKT2 and AKT3.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Qu
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007124:Immunoenzyme Techniques; D019344:Lactic Acid / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D019344:Lactic Acid; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: AKT; Warburg effect; epithelial ovarian cancer; miR-29b; microRNA