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Hepatitis B virus X protein induces hypermethylation of p16(INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis.
J Viral Hepat. 2010 Feb 01; 17(2):98-107.JV

Abstract

The aim of the present study was to authenticate the involvement of DNA methyltransferases (DNMTs) and methyl-CpG binding domain protein 2 (MBD2) in the process of HBx induced p16(INK4A) promoter hypermethylation in HBV-related hepatocellular carcinoma (HCC) and their corresponding noncancerous liver tissues. Eighty-eight fresh tissue specimens of surgically resected HBV-associated HCC and their corresponding noncancerous liver tissues were studied. The methylation status of the p16(INK4A) promoter was determined by methylation-specific polymerase chain reaction (MSP). Reverse transcription and real-time polymerase chain reaction (RT-PCR) showed the expression of DNMTs, MBD2 and HBx. Western blot and immunohistochemistry were used for the protein analysis of HBx, DNMT1, DNMT3A and P16. Tissue HBV-DNA levels were determined by RT-PCR. HBV genotype was examined by nested PCR and restriction fragment length polymorphism (RFLP). In the corresponding noncancerous liver tissues, higher HBx expression was associated with the hypermethylation of the p16(INK4A) promoter. HBx was positively correlated with the DNMT1 and DNMT3A at both the mRNA and protein level. Furthermore, HBx, DNMT1 and DNMT3A protein expression were negatively correlated with p16 protein expression. In HCC tissues, HBx was positively correlated with DNMT1 and DNMT3A at both mRNA and protein level, but HBx expression did not correlate with hypermethylation of the p16(INK4A) promoter or p16 protein expression. The methylation status of the p16(INK4A) promoter did not correlate with clinicopathological characteristics. DNMT1 and DNMT3A may play important roles in the process of HBx inducing hypermethylation of the p16(INK4A) promoter in the early stages of HBV-associated HCC. HBx-DNMTs-p16(INK4A) promoter hypermethylation may constitute a mechanism for tumorigenesis during HBV-associated hepatocarcinogenesis.

Authors+Show Affiliations

Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China.No 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

19732323

Citation

Zhu, Y-Z, et al. "Hepatitis B Virus X Protein Induces Hypermethylation of p16(INK4A) Promoter Via DNA Methyltransferases in the Early Stage of HBV-associated Hepatocarcinogenesis." Journal of Viral Hepatitis, vol. 17, no. 2, 2010, pp. 98-107.
Zhu YZ, Zhu R, Fan J, et al. Hepatitis B virus X protein induces hypermethylation of p16(INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis. J Viral Hepat. 2010;17(2):98-107.
Zhu, Y. Z., Zhu, R., Fan, J., Pan, Q., Li, H., Chen, Q., & Zhu, H. G. (2010). Hepatitis B virus X protein induces hypermethylation of p16(INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis. Journal of Viral Hepatitis, 17(2), 98-107. https://doi.org/10.1111/j.1365-2893.2009.01156.x
Zhu YZ, et al. Hepatitis B Virus X Protein Induces Hypermethylation of p16(INK4A) Promoter Via DNA Methyltransferases in the Early Stage of HBV-associated Hepatocarcinogenesis. J Viral Hepat. 2010 Feb 1;17(2):98-107. PubMed PMID: 19732323.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis B virus X protein induces hypermethylation of p16(INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis. AU - Zhu,Y-Z, AU - Zhu,R, AU - Fan,J, AU - Pan,Q, AU - Li,H, AU - Chen,Q, AU - Zhu,H-G, Y1 - 2009/09/02/ PY - 2009/9/8/entrez PY - 2009/9/8/pubmed PY - 2010/4/8/medline SP - 98 EP - 107 JF - Journal of viral hepatitis JO - J. Viral Hepat. VL - 17 IS - 2 N2 - The aim of the present study was to authenticate the involvement of DNA methyltransferases (DNMTs) and methyl-CpG binding domain protein 2 (MBD2) in the process of HBx induced p16(INK4A) promoter hypermethylation in HBV-related hepatocellular carcinoma (HCC) and their corresponding noncancerous liver tissues. Eighty-eight fresh tissue specimens of surgically resected HBV-associated HCC and their corresponding noncancerous liver tissues were studied. The methylation status of the p16(INK4A) promoter was determined by methylation-specific polymerase chain reaction (MSP). Reverse transcription and real-time polymerase chain reaction (RT-PCR) showed the expression of DNMTs, MBD2 and HBx. Western blot and immunohistochemistry were used for the protein analysis of HBx, DNMT1, DNMT3A and P16. Tissue HBV-DNA levels were determined by RT-PCR. HBV genotype was examined by nested PCR and restriction fragment length polymorphism (RFLP). In the corresponding noncancerous liver tissues, higher HBx expression was associated with the hypermethylation of the p16(INK4A) promoter. HBx was positively correlated with the DNMT1 and DNMT3A at both the mRNA and protein level. Furthermore, HBx, DNMT1 and DNMT3A protein expression were negatively correlated with p16 protein expression. In HCC tissues, HBx was positively correlated with DNMT1 and DNMT3A at both mRNA and protein level, but HBx expression did not correlate with hypermethylation of the p16(INK4A) promoter or p16 protein expression. The methylation status of the p16(INK4A) promoter did not correlate with clinicopathological characteristics. DNMT1 and DNMT3A may play important roles in the process of HBx inducing hypermethylation of the p16(INK4A) promoter in the early stages of HBV-associated HCC. HBx-DNMTs-p16(INK4A) promoter hypermethylation may constitute a mechanism for tumorigenesis during HBV-associated hepatocarcinogenesis. SN - 1365-2893 UR - https://www.unboundmedicine.com/medline/citation/19732323/Hepatitis_B_virus_X_protein_induces_hypermethylation_of_p16_INK4A__promoter_via_DNA_methyltransferases_in_the_early_stage_of_HBV_associated_hepatocarcinogenesis_ L2 - https://doi.org/10.1111/j.1365-2893.2009.01156.x DB - PRIME DP - Unbound Medicine ER -