These authors contributed equally to this work.
Hepatocyte nuclear factor-4α reverses malignancy of hepatocellular carcinoma through regulating miR-134 in the DLK1-DIO3 region
Article first published online: 22 OCT 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 6, pages 1964–1976, December 2013
How to Cite
Yin, C., Wang, P.-Q., Xu, W.-P., Yang, Y., Zhang, Q., Ning, B.-F., Zhang, P.-P., Zhou, W.-P., Xie, W.-F., Chen, W.-S. and Zhang, X. (2013), Hepatocyte nuclear factor-4α reverses malignancy of hepatocellular carcinoma through regulating miR-134 in the DLK1-DIO3 region. Hepatology, 58: 1964–1976. doi: 10.1002/hep.26573
Potential conflict of interest: Nothing to report.
Supported by the National Natural Science Foundation of China (81071842, 81270033; Key Program 81230011; Creative Research Groups 30921006), the China National Key Projects for Infectious Disease (2013ZX10002007-007), the Shanghai Science and Technology Committee for Key Projects (11JC1416200 and 10431903600), and the Rising-Star Program (11QA1408800).
- Issue published online: 26 NOV 2013
- Article first published online: 22 OCT 2013
- Accepted manuscript online: 14 JUN 2013 09:49AM EST
- Manuscript Accepted: 30 MAY 2013
- Manuscript Received: 6 FEB 2013
- National Natural Science Foundation of China,. Grant Numbers: 81071842, 81270033
- Key Program. Grant Number: 81230011
- Creative Research Groups. Grant Number: 30921006
- China National Key Projects for Infectious Disease. Grant Number: 2013ZX10002007-007
- Shanghai Science and Technology Committee for Key Projects. Grant Numbers: 11JC1416200, 10431903600
- Rising-Star Program. Grant Number: 11QA1408800
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. 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; 58:1964–1976)