MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway.
Non-alcoholic fatty liver disease (NAFLD) is a major risk factor for hepatocellular carcinoma (HCC). However, the mechanistic pathways that link both disorders are essentially unknown.



Our study was designed to investigate the role of microRNA-21 in the pathogenesis of NAFLD and its potential involvement in HCC.



Wildtype mice maintained on a high fat diet (HFD) received tail vein injections of microRNA-21-anti-sense oligonucleotide (ASO) or miR-21 mismatched ASO for 4 or 8 weeks. Livers were collected after that time period for lipid content and gene expression analysis. Human hepatoma HepG2 cells incubated with oleate were used to study the role of miR-21 in lipogenesis and analysed with Nile-Red staining. microRNA-21 function in carcinogenesis was determined by soft-agar colony formation, cell cycle analysis and xenograft tumour assay using HepG2 cells.



The expression of microRNA-21 was increased in the livers of HFD-treated mice and human HepG2 cells incubated with fatty acid. MicroRNA-21 knockdown in those mice and HepG2 cells impaired lipid accumulation and growth of xenograft tumour. Further studies revealed thatHbp1was a novel target of microRNA-21 and a transcriptional activator ofp53. It is well established that p53 is a tumour suppressor and an inhibitor of lipogenesis by inhibitingSrebp1c. As expected, microRNA-21 knockdown led to increasedHBP1andp53and subsequently reduced lipogenesis and delayed G1/S transition, and the additional treatment ofHBP1-siRNA antagonised the effect of microRNA-21-ASO, suggesting thatHBP1mediated the inhibitory effects of microRNA-21-ASO on both hepatic lipid accumulation and hepatocarcinogenesis. Mechanistically, microRNA-21 knockdown inducedp53transcription, which subsequently reduced expression of genes controlling lipogenesis and cell cycle transition. In contrast, the opposite result was observed with overexpression of microRNA-21, which preventedp53transcription.



Our findings reveal a novel mechanism by which microRNA-21, in part, promotes hepatic lipid accumulation and cancer progression by interacting with theHbp1-p53-Srebp1cpathway and suggest the potential therapeutic value of microRNA-21-ASO for both disorders.
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Heng
H
Wu
Agency for Science Technology and Research, Singapore, Singapore.
Raymond
R
Ng
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
Xin
X
Chen
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.|Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
Clifford J
CJ
Steer
Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Guisheng
G
Song
D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D051780:Sterol Regulatory Element Binding Protein 1; D016159:Tumor Suppressor Protein p53
HEPATOCELLULAR CARCINOMA; HEPATOCYTE; MOLECULAR BIOLOGY; NONALCOHOLIC STEATOHEPATITIS