Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224

Sheng Hui Lan, Shan Ying Wu, Roberto Zuchini, Xi Zhang Lin, Ih Jen Su, Ting Fen Tsai, Yen Ju Lin, Cheng Tao Wu, Hsiao Sheng Liu

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117 Citations (Scopus)

Abstract

In hepatocellular carcinoma (HCC), dysregulated expression of microRNA-224 (miR-224) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. In this study we determined that autophagy is down-regulated and inversely correlated with miR-224 expression in hepatitis B virus (HBV)-associated HCC patient specimens. These results were confirmed in liver tumors of HBV X gene transgenic mice. Furthermore, miR-224 was preferentially recruited and degraded during autophagic progression demonstrated by real-time polymerase chain reaction and miRNA in situ hybridization electron microscopy after extraction of autophagosomes. Our in vitro study demonstrated that miR-224 played an oncogenic role in hepatoma cell migration and tumor formation through silencing its target gene Smad4. In HCC patients, the expression of low-Atg5, high-miR-224, and low-Smad4 showed significant correlation with HBV infection and a poor overall survival rate. Autophagy-mediated miR-224 degradation and liver tumor suppression were further confirmed by the autophagy inducer amiodarone and miR-224 antagonist using an orthotopic SD rat model. Conclusion: A noncanonical pathway links autophagy, miR-224, Smad4, and HBV-associated HCC. These findings open a new avenue for the treatment of HCC.

Original languageEnglish
Pages (from-to)505-517
Number of pages13
JournalHepatology
Volume59
Issue number2
DOIs
Publication statusPublished - 2014 Feb 1

All Science Journal Classification (ASJC) codes

  • Hepatology

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    Lan, S. H., Wu, S. Y., Zuchini, R., Lin, X. Z., Su, I. J., Tsai, T. F., Lin, Y. J., Wu, C. T., & Liu, H. S. (2014). Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. Hepatology, 59(2), 505-517. https://doi.org/10.1002/hep.26659