title: Autophagy-preferential degradation of MIR224 participates in hepatocellular carcinoma tumorigenesis.
abstract: Autophagy and microRNA (miRNA) are important regulators during cancer cell tumorigenesis. Impaired autophagy and high expression of the oncogenic microRNA MIR224 are prevalent in hepatocellular carcinoma (HCC); however, the relationship between the 2 phenomena remains elusive. In this study, we are the first to reveal that autophagy selectively regulates MIR224 expression through an autophagosome-mediated degradation system. Based on this finding, we further demonstrated that in hepatitis B virus (HBV)-related HCC, aberrant autophagy (low autophagic activity) results in accumulation of MIR224 and decreased expression of the target gene Smad4, which leads to increased cell migration and tumor formation. Preferential recruitment of MIR224 into the autophagosome was clearly demonstrated by a) miRNA in situ hybridization under confocal microscopy, and b) immunogold labeling of MIR224 under electron microscopy compared with a ubiquitously expressed microRNA MIRlet7e/let-7. Furthermore, we found that off-label use of amiodarone, an antiarrhythmic agent, effectively suppressed HCC tumorigenesis through autophagy-mediated MIR224 degradation both in vitro and in vivo. In summary, we identified amiodarone as a new autophagy inducer, which may provide an alternative approach in HCC therapy through a novel tumor suppression mechanism.
authors: Department of Microbiology and Immunology; National Cheng Kung University; Tainan, Taiwan.
authors: Sheng-Hui
authors: SH
authors: Lan
authors: Department of Microbiology and Immunology; National Cheng Kung University; Tainan, Taiwan.
authors: Shan-Ying
authors: SY
authors: Wu
authors: Department of Microbiology and Immunology; National Cheng Kung University; Tainan, Taiwan.
authors: Roberto
authors: R
authors: Zuchini
authors: Department of Microbiology and Immunology; National Cheng Kung University; Tainan, Taiwan.
authors: Xi-Zhang
authors: XZ
authors: Lin
authors: National Health Research Institutes; Tainan, Taiwan.
authors: Ih-Jen
authors: IJ
authors: Su
authors: Department of Life Sciences and Institute of Genome Sciences; National Yang-Ming University; Taipei, Taiwan.
authors: Ting-Fen
authors: TF
authors: Tsai
authors: Industrial Technology Research Institute; Hsinchu, Taiwan.
authors: Yen-Ju
authors: YJ
authors: Lin
authors: Institute of Biomedical Informatics; National Yang-Ming University; Taipei, Taiwan.
authors: Cheng-Tao
authors: CT
authors: Wu
authors: Department of Microbiology and Immunology; National Cheng Kung University; Tainan, Taiwan.
authors: Hsiao-Sheng
authors: HS
authors: Liu
mesh_terms: D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006515:Hepatitis B virus; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D035683:MicroRNAs / Q000378:metabolism*
chemical_list: C546140:MIRN224 microRNA, human; D035683:MicroRNAs
keywords: HBV; HCC; autophagy; miR-224; miRNA