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Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells.
Hepatology 2012; 56(6):2051-9Hep

Abstract

Hepatitis B virus X protein (HBx) plays critical roles in the development of hepatocellular carcinogenesis (HCC). Yes-associated protein (YAP), a downstream effector of the Hippo-signaling pathway, is an important human oncogene. In the present article, we report that YAP is involved in the hepatocarcinogenesis mediated by HBx. We demonstrated that the expression of YAP was dramatically elevated in clinical HCC samples, hepatitis B virus (HBV)-infected hepatoma HepG2.2.15 cell line, and liver cancer tissues of HBx-transgenic mice. Meanwhile, we found that overexpression of HBx resulted in the up-regulation of YAP in stably HBx-transfected HepG2/H7402 hepatoma cell lines, whereas HBx RNA interference reduced YAP expression in a dose-dependent manner in the above-mentioned cell lines, suggesting that HBx up-regulates YAP. Then, we investigated the mechanism underlying the up-regulation of YAP by HBx. Luciferase reporter gene assays revealed that the promoter region of YAP regulated by HBx was located at nt -232/+115 containing cyclic adenosine monophosphate response element-binding protein (CREB) element. Chromatin immunoprecipitation (ChIP) demonstrated that HBx was able to bind to the promoter of YAP, whereas it failed to work when CREB was silenced. Moreover, we confirmed that HBx activated the YAP promoter through CREB by electrophoretic mobility shift assay and luciferase reporter gene assays. Surprisingly, we found that YAP short interfering RNA was able to remarkably block the HBx-enhanced growth of hepatoma cells in vivo and in vitro.

CONCLUSION

YAP is a key driver gene in HBx-induced hepatocarcinogenesis in a CREB-dependent manner. YAP may serve as a novel target in HBV-associated HCC therapy.

Authors+Show Affiliations

Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22707013

Citation

Zhang, Tao, et al. "Hepatitis B Virus X Protein Modulates Oncogene Yes-associated Protein By CREB to Promote Growth of Hepatoma Cells." Hepatology (Baltimore, Md.), vol. 56, no. 6, 2012, pp. 2051-9.
Zhang T, Zhang J, You X, et al. Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells. Hepatology. 2012;56(6):2051-9.
Zhang, T., Zhang, J., You, X., Liu, Q., Du, Y., Gao, Y., ... Zhang, X. (2012). Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells. Hepatology (Baltimore, Md.), 56(6), pp. 2051-9. doi:10.1002/hep.25899.
Zhang T, et al. Hepatitis B Virus X Protein Modulates Oncogene Yes-associated Protein By CREB to Promote Growth of Hepatoma Cells. Hepatology. 2012;56(6):2051-9. PubMed PMID: 22707013.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells. AU - Zhang,Tao, AU - Zhang,Junping, AU - You,Xiaona, AU - Liu,Qian, AU - Du,Yumei, AU - Gao,Yuen, AU - Shan,Changliang, AU - Kong,Guangyao, AU - Wang,Youliang, AU - Yang,Xiao, AU - Ye,Lihong, AU - Zhang,Xiaodong, Y1 - 2012/11/13/ PY - 2012/01/16/received PY - 2012/05/28/accepted PY - 2012/6/19/entrez PY - 2012/6/19/pubmed PY - 2013/3/1/medline SP - 2051 EP - 9 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 56 IS - 6 N2 - UNLABELLED: Hepatitis B virus X protein (HBx) plays critical roles in the development of hepatocellular carcinogenesis (HCC). Yes-associated protein (YAP), a downstream effector of the Hippo-signaling pathway, is an important human oncogene. In the present article, we report that YAP is involved in the hepatocarcinogenesis mediated by HBx. We demonstrated that the expression of YAP was dramatically elevated in clinical HCC samples, hepatitis B virus (HBV)-infected hepatoma HepG2.2.15 cell line, and liver cancer tissues of HBx-transgenic mice. Meanwhile, we found that overexpression of HBx resulted in the up-regulation of YAP in stably HBx-transfected HepG2/H7402 hepatoma cell lines, whereas HBx RNA interference reduced YAP expression in a dose-dependent manner in the above-mentioned cell lines, suggesting that HBx up-regulates YAP. Then, we investigated the mechanism underlying the up-regulation of YAP by HBx. Luciferase reporter gene assays revealed that the promoter region of YAP regulated by HBx was located at nt -232/+115 containing cyclic adenosine monophosphate response element-binding protein (CREB) element. Chromatin immunoprecipitation (ChIP) demonstrated that HBx was able to bind to the promoter of YAP, whereas it failed to work when CREB was silenced. Moreover, we confirmed that HBx activated the YAP promoter through CREB by electrophoretic mobility shift assay and luciferase reporter gene assays. Surprisingly, we found that YAP short interfering RNA was able to remarkably block the HBx-enhanced growth of hepatoma cells in vivo and in vitro. CONCLUSION: YAP is a key driver gene in HBx-induced hepatocarcinogenesis in a CREB-dependent manner. YAP may serve as a novel target in HBV-associated HCC therapy. SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/22707013/Hepatitis_B_virus_X_protein_modulates_oncogene_Yes_associated_protein_by_CREB_to_promote_growth_of_hepatoma_cells_ L2 - https://doi.org/10.1002/hep.25899 DB - PRIME DP - Unbound Medicine ER -