title: MiR-338-3p inhibits hepatocarcinoma cells and sensitizes these cells to sorafenib by targeting hypoxia-induced factor 1α.
abstract: Hypoxia is a common feature of solid tumors and an important contributor to anti-tumor drug resistance. Hypoxia inducible factor-1 (HIF-1) is one of the key mediators of the hypoxia signaling pathway, and was recently proven to be required for sorafenib resistance in hepatocarcinoma (HCC). MicroRNAs have emerged as important posttranslational regulators in HCC. It was reported that miR-338-3p levels are associated with clinical aggressiveness of HCC. However, the roles of miR-338-3p in HCC disease and resistance to its therapeutic drugs are unknown. In this study, we found that miR-338-3p was frequently down-regulated in 14 HCC clinical samples and five cell lines. Overexpression of miR-338-3p inhibited HIF-1α 3'-UTR luciferase activity and HIF-1α protein levels in HepG2, SMMC-7721, and Huh7 cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally, HIF-1α overexpression rescued and HIF-1α knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore, miR-338-3p sensitized HCC cells to sorafenib in vitro and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1α. Collectively, miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1α. Our data indicate that miR-338-3p could be a potential candidate for HCC therapeutics.
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine, The Heilongjiang Provincial Hospital, Harbin, Heilongjiang, P.R. China.
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.
authors.forename: Songyan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhan
authors.affiliation: Department of Operations, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.
authors.forename: Shujie
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C532050:MIRN338 microRNA, human; D035683:MicroRNAs; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D009536:Niacinamide; D000077157:Sorafenib