期刊
HEPATOLOGY
卷 59, 期 2, 页码 505-517出版社
WILEY-BLACKWELL
DOI: 10.1002/hep.26659
关键词
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资金
- Headquarters of University Advancement, National Cheng Kung University [D100similar to101-35001]
- National Science Council [NSC-99-2745-B-006-002, NSC100-2320-B-006-022, NSC101-2320-B006-025-MY3]
- National Science and Technology Development Fund [97-EC-17-A-31-F1-0695]
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. (Hepatology 2014;59:505-517)
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