title: Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224.
abstract: In hepatocellular carcinoma (HCC), dysregulated expression of microRNA-224 (miR-224) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. In this study we determined that autophagy is down-regulated and inversely correlated with miR-224 expression in hepatitis B virus (HBV)-associated HCC patient specimens. These results were confirmed in liver tumors of HBV X gene transgenic mice. Furthermore, miR-224 was preferentially recruited and degraded during autophagic progression demonstrated by real-time polymerase chain reaction and miRNA in situ hybridization electron microscopy after extraction of autophagosomes. Our in vitro study demonstrated that miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. In HCC patients, the expression of low-Atg5, high-miR-224, and low-Smad4 showed significant correlation with HBV infection and a poor overall survival rate. Autophagy-mediated miR-224 degradation and liver tumor suppression were further confirmed by the autophagy inducer amiodarone and miR-224 antagonist using an orthotopic SD rat model.
  
  
  CONCLUSIONS
  A noncanonical pathway links autophagy, miR-224, Smad4, and HBV-associated HCC. These findings open a new avenue for the treatment of HCC.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Sheng-Hui
authors.initials: SH
authors.lastname: Lan
authors.forename: Shan-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Roberto
authors.initials: R
authors.lastname: Zuchini
authors.forename: Xi-Zhang
authors.initials: XZ
authors.lastname: Lin
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
authors.forename: Ting-Fen
authors.initials: TF
authors.lastname: Tsai
authors.forename: Yen-Ju
authors.initials: YJ
authors.lastname: Lin
authors.forename: Cheng-Tao
authors.initials: CT
authors.lastname: Wu
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
mesh_terms: D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D063646:Carcinogenesis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D015536:Down-Regulation; D006509:Hepatitis B / Q000150:complications; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008854:Microscopy, Electron; D051381:Rats; D017207:Rats, Sprague-Dawley; D051901:Smad4 Protein / Q000378:metabolism
chemical_list: C546140:MIRN224 microRNA, human; C584584:MIRN224 microRNA, mouse; C000588626:MIRN224 microRNA, rat; D035683:MicroRNAs; D051901:Smad4 Protein; D000638:Amiodarone
references.citation: FASEB J. 2012 Jul;26(7):3032-41
references.pmid: 22459148
references.citation: PLoS One. 2009 Sep 22;4(9):e7124
references.pmid: 19771169
references.citation: J Virol. 2012 Dec;86(23):12717-30
references.pmid: 22973026
references.citation: Autophagy. 2010 May;6(4):542-7
references.pmid: 20505360
references.citation: Nat Rev Mol Cell Biol. 2005 May;6(5):376-85
references.pmid: 15852042
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4383-8
references.pmid: 20142477
references.citation: Nat Cell Biol. 2009 Sep;11(9):1150-6
references.pmid: 19684574
references.citation: Int J Biochem Cell Biol. 2012 May;44(5):733-6
references.pmid: 22342941
references.citation: J Gastroenterol Hepatol. 2012 Mar;27 Suppl 2:10-4
references.pmid: 22320909
references.citation: Cell. 2009 Aug 21;138(4):696-708
references.pmid: 19703396
references.citation: Curr Opin Virol. 2012 Aug;2(4):467-73
references.pmid: 22722078
references.citation: Cancer Cell. 2006 Aug;10(2):99-111
references.pmid: 16904609
references.citation: Lab Invest. 2012 Oct;92(10):1390-7
references.pmid: 22890556
references.citation: J Pak Med Assoc. 2012 Mar;62(3):268-72
references.pmid: 22764462
references.citation: Mol Endocrinol. 2010 Mar;24(3):540-51
references.pmid: 20118412
references.citation: J Clin Invest. 2003 Dec;112(12):1809-20
references.pmid: 14638851
references.citation: J Hepatol. 2010 Dec;53(6):1123-34
references.pmid: 20810185
references.citation: Genes Dev. 2007 Jun 1;21(11):1367-81
references.pmid: 17510285
references.citation: Hepatology. 2012 Aug;56(2):632-43
references.pmid: 22392644
references.citation: Nat Cell Biol. 2012 Dec;14(12):1314-21
references.pmid: 23143396
references.citation: Genes Dev. 2011 Apr 15;25(8):795-800
references.pmid: 21498569
references.citation: J Gastroenterol Hepatol. 2013 Mar;28(3):565-75
references.pmid: 22989374
references.citation: J Hepatol. 2011 Jun;54(6):1177-84
references.pmid: 21145831
references.citation: Biochem Biophys Res Commun. 2006 Feb 17;340(3):916-28
references.pmid: 16403455
references.citation: Autophagy. 2010 Apr;6(3):322-9
references.pmid: 20224296
references.citation: Neuro Oncol. 2011 Mar;13(3):267-79
references.pmid: 21292685
references.citation: Semin Cell Dev Biol. 2012 Jun;23(4):395-401
references.pmid: 22281437
references.citation: Cancer Res. 2008 Nov 15;68(22):9167-75
references.pmid: 19010888
references.citation: J Gastroenterol Hepatol. 2010 Jan;25(1):164-71
references.pmid: 19793168
references.citation: Gastroenterology. 2010 Mar;138(3):969-80.e1-3
references.pmid: 19909744
references.citation: J Virol. 2011 Jul;85(13):6319-33
references.pmid: 21507968
references.citation: Hepatology. 2008 Dec;48(6):2047-63
references.pmid: 19003900
references.citation: Science. 2008 Mar 28;319(5871):1782-4
references.pmid: 18369134