title: MicroRNA-100 promotes the autophagy of hepatocellular carcinoma cells by inhibiting the expression of mTOR and IGF-1R.
abstract: We found that restoration of miR-100 expression resulted in accumulation of LC3B-II and decrease of p62 in hepatocellular carcinoma (HCC) cells, whereas antagonism of miR-100 reduced the level of LC3B-II. Moreover, a significant correlation between miR-100 downregulation and p62 upregulation was observed in human HCC tissues, suggesting an autophagy-promoting effect of miR-100. Subsequent investigations disclosed that knockdown of Atg7 but not Beclin-1 attenuated the miR-100-induced LC3B-II elevation. Furthermore, miR-100 overexpression caused massive cell death, which was abrogated by both the Atg7 silencing and chloroquine treatment. Simultaneously, miR-100 expression led to increased fraction of cells with Annexin V-staining and loss of mitochondrial potential, implying that miR-100 may promote the Atg7-dependent autophagy and subsequent apoptotic cell death. Consistently, mouse xenograft models revealed that miR-100 inhibited the in vivo growth of HCC cells. We further showed that miR-100 suppressed the expression of mTOR and IGF-1R by binding to their 3' untranslated region, and knockdown of mTOR or IGF-1R phenocopied the pro-autophagy effect of miR-100, indicating that miR-100 may promote autophagy by reducing mTOR and IGF-1R level. Collectively, our data uncover a new regulatory mechanism of autophagy and a novel function of miR-100, and provide a potential therapeutic target for HCC.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Guangzhou, P.R. China; These authors contributed equally to this work.
authors.forename: Yi-Yuan
authors.initials: YY
authors.lastname: Ge
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Guangzhou, P.R. China; These authors contributed equally to this work.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Guangzhou, P.R.
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Guangzhou, P.R. China; Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital; Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Gong
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Guangzhou, P.R.
authors.forename: Chunxian
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Guangzhou, P.R.
authors.forename: Jine
authors.initials: J
authors.lastname: Yang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Guangzhou, P.R. China; Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital; Sun Yat-sen University, Guangzhou, P.R. China.
authors.forename: Shi-Mei
authors.initials: SM
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D056945:Hep G2 Cells; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
chemical_list: C544266:MIRN100 microRNA, human; D035683:MicroRNAs; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases