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

Research output: Contribution to journalArticle

110 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

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Autophagy
MicroRNAs
Hepatitis B virus
Hepatocellular Carcinoma
Carcinogenesis
Neoplasms
Amiodarone
Liver
Virus Diseases
Transgenic Mice
Genes
Cell Movement
In Situ Hybridization
Real-Time Polymerase Chain Reaction
Electron Microscopy
Survival Rate

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Lan, Sheng Hui ; Wu, Shan Ying ; Zuchini, Roberto ; Lin, Xi-Zhang ; Su, Ih Jen ; Tsai, Ting Fen ; Lin, Yen Ju ; Wu, Cheng Tao ; Liu, Hsiao-Sheng. / Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. In: Hepatology. 2014 ; Vol. 59, No. 2. pp. 505-517.
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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.",
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Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. / Lan, Sheng Hui; Wu, Shan Ying; Zuchini, Roberto; Lin, Xi-Zhang; Su, Ih Jen; Tsai, Ting Fen; Lin, Yen Ju; Wu, Cheng Tao; Liu, Hsiao-Sheng.

In: Hepatology, Vol. 59, No. 2, 01.02.2014, p. 505-517.

Research output: Contribution to journalArticle

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AU - Tsai, Ting Fen

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