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The role of androgen receptor in HBV related hepatocellular carcinoma

The role of androgen receptor in HBV related hepatocellular carcinoma. The relationship between HBV and HCC. Chronic hepatitis B virus (HBV) infection as a leading risk factor for HCC and about 53% of HCC cases in the world are related to HBV. J Hepatol. 2006 Oct;45(4):529-38.

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The role of androgen receptor in HBV related hepatocellular carcinoma

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  1. The role of androgen receptor in HBV related hepatocellular carcinoma

  2. The relationship between HBV and HCC Chronic hepatitis B virus (HBV) infection as a leading risk factor for HCCand about 53% of HCC cases in the world are related to HBV J Hepatol. 2006 Oct;45(4):529-38 Hepatitis B Virus can efficiently promote hepatocarcinogenesis initiated by the carcinogen in transgenic mice Hepatology 2007;45:16-21

  3. Sexual difference in HBV related HCC The male/female ratio was 7.8 in the HBV related HCC patients European Journal of Cancer 2006; 42; 2524–2529 What is the role of androgen receptor in HBV related HCC?

  4. Generation of HBV Liver AR Knockout (HBV-LARKO) mice

  5. Animal model I.P. injection of Diethylnitrosamine (DEN) 2mg/g HBV wt or HBV-LARKO mice 32 40 (weeks) 12 days Sacrifice mice and measure tumor incidence and foci Inject DEN

  6. Loss of hepatic AR suppress low DEN-HBV induced HCC (A) (B) N=5 Tumor foci number N=3 (C) (D) LW/BW 4/7 Tumor incidence 1/4

  7. Epidemiological studies of HBV replication and HCC Active HBV replication correlates significantly with the risk of the development of hepatocellular carcinoma (HCC) Semin Liver Dis. 2006 May;26(2):142-52 Sustained reduction of HBV replication lowers the risk of HCC in HBV-related cirrhosis Gastroenterology. 2004 Nov;127:S35-50

  8. AR enhance HBV replication in the liver cells (A) (B) HBV DNA in liver tissues HBV Pre C/ pregenome RNA in liver tissues N=5 Fold change to wild type Fold change to wild type N=7 HBV-Wt HBV-LARKO HBV-wt HBV-LARKO (C) AR increase HBV DNA amount in HCC cell line C AR(2.5 mg) AR(5mg) HBV DNA

  9. Nucleocapsid (Core) promoter and HBV replication The core gene (C-gene) promoter and regulatory sequences are essential for the synthesis of the pregenomic which is the template required for replication

  10. AR and HBx enhance HBV core promoter activity cooperatively (A) (B) AR increase Core promoter activity HBx increase Core promoter activity Relative Luciferase activity Relative Luciferase activity pCMV-HBx - 0.1 0.2 0.4 (mg) pSG5-AR - 0.1 0.4 (mg) (C) (D) AR and HBx increase Core promoter activity (SK-Hep1 cells) AR and HBx increase Core promoter activity (HepG2) Relative Luciferase activity Relative Luciferase activity HBx(mg) - 0.2 0.2 0.2 AR (mg) - - 0.1 0.2 Skpar SK-HBx KAR3-HBx

  11. Conclusions • AR promote the HBV related hepatocarcinogenesis • AR and HBx can cooperatively increase core promoter activity to enhance HBV replication

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