title: Hepatocyte nuclear factor-4α reverses malignancy of hepatocellular carcinoma through regulating miR-134 in the DLK1-DIO3 region.
abstract: Hepatocyte nuclear factor-4α (HNF4α) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis. There is striking suppression of hepatocellular carcinoma (HCC) by HNF4α, although the mechanisms by which HNF4α reverses HCC malignancy are largely unknown. Herein, we demonstrate that HNF4α administration to HCC cells resulted in elevated levels of 28 mature microRNAs (miRNAs) from the miR-379-656 cluster, which is located in the delta-like 1 homolog (DLK1) -iodothyronine deiodinase 3 (DIO3) locus on human chromosome 14q32. Consistent with the reduction of HNF4α, these miRNAs were down-regulated in human HCC tissue. HNF4α regulated the transcription of the miR-379-656 cluster by directly binding to its response element in the DLK1-DIO3 region. Interestingly, several miRNAs in this cluster inhibited proliferation and metastasis of HCC cells in vitro. As a representative miRNA in this cluster, miR-134 exerted a dramatically suppressive effect on HCC malignancy by down-regulating the oncoprotein, KRAS. Moreover, miR-134 markedly diminished HCC tumorigenicity and displayed a significant antitumor effect in vivo. In addition, inhibition of endogenous miR-134 partially reversed the suppressive effects of HNF4α on KRAS expression and HCC malignancy. Furthermore, a positive correlation between HNF4α and miR-134 levels was observed during hepatocarcinogenesis in rats, and decreases in miR-134 levels were significantly associated with the aggressive behavior of human HCCs.
  
  
  CONCLUSIONS
  Our data highlight the importance of the miR-379-656 cluster in the inhibitory effect of HNF4α on HCC, and suggest that regulation of the HNF4α-miRNA cascade may have beneficial effects in the treatment of HCC.
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Yin
authors.forename: Pei-Qin
authors.initials: PQ
authors.lastname: Wang
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Xu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Bei-Fang
authors.initials: BF
authors.lastname: Ning
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Zhang
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Zhou
authors.forename: Wei-Fen
authors.initials: WF
authors.lastname: Xie
authors.forename: Wan-Sheng
authors.initials: WS
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000502:physiology; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D051381:Rats; D018631:ras Proteins / Q000378:metabolism
chemical_list: D051557:Hepatocyte Nuclear Factor 4; C117307:KRAS protein, human; C569273:MIRN134 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins