Document Detail


Hepatocyte nuclear factor-4α reverses malignancy of hepatocellular carcinoma through regulating miR-134 in the DLK1-DIO3 region.
MedLine Citation:
PMID:  23775631     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Hepatocyte nuclear factor-4α (HNF4α) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis. A previous study from this laboratory demonstrated striking suppression of hepatocellular carcinoma (HCC) by HNF4α, although the mechanisms by which HNF4α reverses HCC malignancy are largely unknown. Herein, we demonstrated that HNF4α administration to HCC cells resulted in elevated levels of 28 mature miRNAs from the miR-379-656 cluster, which is located in the DLK1-DIO3 locus on human chromosome 14q32. Consistent with the reduction of HNF4α, these miRNAs were downregulated 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 downregulating the onco-protein, 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 behaviors of human HCCs. Conclusion: 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. (HEPATOLOGY 2013.).
Authors:
Chuan Yin; Pei-Qin Wang; Wen-Ping Xu; Yuan Yang; Qing Zhang; Bei-Fang Ning; Ping-Ping Zhang; Wei-Ping Zhou; Wei-Fen Xie; Wan-Sheng Chen; Xin Zhang
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-6-14
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  -     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-6-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013 American Association for the Study of Liver Diseases.
Affiliation:
Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
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