Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis

Overview

Journal J Clin Transl Hepatol

Specialty Gastroenterology

Date 2021 Aug 27

PMID 34447675

Citations 4

Authors

Yongdong Niu

Shaohua Fan

Qin Luo

Liming Chen

Danmei Huang

Wenjun Chang

Wenxin Qin

Ganggang Shi

Affiliations

Soon will be listed here.

Abstract

Background And Aims: Hepatitis B virus (HBV) infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics, by unknown mechanisms, in the generation of hepatocellular carcinoma. The pregnane X receptor (PXR) is a key regulator of the body's defense against xenobiotics, including xenobiotic carcinogens and clinical drugs. In this study, we aimed to investigate the molecular mechanisms of HBV X protein (HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.

Methods: The expression profile of PXR-cytochrome p450 3A4 (CYP3A4) signaling was determined by PCR, western blotting, and tissue microarray. Cell viability and aflatoxin B1 (AFB1) cytotoxicity were measured using the cell counting kit-8 assay. Target gene expression was evaluated using transient transfection and real time-PCR. The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.

Results: HBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione S-transferase Mu 1 (GSTM1) in cell lines. Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin (IL)-11:IL-11 receptor subunit alpha-1 (IL11RA-1)-mediated inflammation in an HBx transgenic model.

Conclusions: Our finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/ GSTM1-KRAS-IL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.

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References

Lereau M, Gouas D, Villar S, Besaratinia A, Hautefeuille A, Berthillon P . Interactions between hepatitis B virus and aflatoxin B(1): effects on p53 induction in HepaRG cells. J Gen Virol. 2011; 93(Pt 3):640-650. DOI: 10.1099/vir.0.032482-0. View

Kotiya D, Jaiswal B, Ghose S, Kaul R, Datta K, Tyagi R . Role of PXR in Hepatic Cancer: Its Influences on Liver Detoxification Capacity and Cancer Progression. PLoS One. 2016; 11(10):e0164087. PMC: 5070842. DOI: 10.1371/journal.pone.0164087. View

Zhang W, He H, Zang M, Wu Q, Zhao H, Lu L . Genetic Features of Aflatoxin-Associated Hepatocellular Carcinoma. Gastroenterology. 2017; 153(1):249-262.e2. DOI: 10.1053/j.gastro.2017.03.024. View

Kamdem L, Meineke I, Godtel-Armbrust U, Brockmoller J, Wojnowski L . Dominant contribution of P450 3A4 to the hepatic carcinogenic activation of aflatoxin B1. Chem Res Toxicol. 2006; 19(4):577-86. DOI: 10.1021/tx050358e. View

Kensler T, Qian G, Chen J, Groopman J . Translational strategies for cancer prevention in liver. Nat Rev Cancer. 2003; 3(5):321-9. DOI: 10.1038/nrc1076. View

Huang J, Deng Q, Wang Q, Li K, Dai J, Li N . Exome sequencing of hepatitis B virus-associated hepatocellular carcinoma. Nat Genet. 2012; 44(10):1117-21. DOI: 10.1038/ng.2391. View

Gross-Steinmeyer K, Stapleton P, Tracy J, Bammler T, Strom S, Eaton D . Sulforaphane- and phenethyl isothiocyanate-induced inhibition of aflatoxin B1-mediated genotoxicity in human hepatocytes: role of GSTM1 genotype and CYP3A4 gene expression. Toxicol Sci. 2010; 116(2):422-32. PMC: 2905401. DOI: 10.1093/toxsci/kfq135. View

Fox J, Feng Y, Theve E, Raczynski A, Fiala J, Doernte A . Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens. Gut. 2009; 59(1):88-97. PMC: 3891362. DOI: 10.1136/gut.2009.183749. View

Li C, Wang Y, Dong W, Xiang S, Liang H, Wang H . Hepatic oval cell lines generate hepatocellular carcinoma following transfection with HBx gene and treatment with aflatoxin B1 in vivo. Cancer Lett. 2011; 311(1):1-10. DOI: 10.1016/j.canlet.2011.05.035. View

10.

Chomarat P, Rice J, Slagle B, Wild C . Hepatitis B virus-induced liver injury and altered expression of carcinogen metabolising enzymes: the role of the HBx protein. Toxicol Lett. 1999; 102-103:595-601. DOI: 10.1016/s0378-4274(98)00254-9. View

11.

Arzumanyan A, Reis H, Feitelson M . Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer. 2013; 13(2):123-35. DOI: 10.1038/nrc3449. View

12.

Cheng J, Ma X, Krausz K, Idle J, Gonzalez F . Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity. Drug Metab Dispos. 2009; 37(8):1611-21. PMC: 2712435. DOI: 10.1124/dmd.109.027565. View

13.

McGlynn K, Hunter K, Levoyer T, Roush J, Wise P, Michielli R . Susceptibility to aflatoxin B1-related primary hepatocellular carcinoma in mice and humans. Cancer Res. 2003; 63(15):4594-601. View

14.

Lian M, Liu Y, Yu S, Qian G, Wan S, Dixon K . Hepatitis B virus x gene and cyanobacterial toxins promote aflatoxin B1-induced hepatotumorigenesis in mice. World J Gastroenterol. 2006; 12(19):3065-72. PMC: 4124383. DOI: 10.3748/wjg.v12.i19.3065. View

15.

Jeannot E, Boorman G, Kosyk O, Bradford B, Shymoniak S, Tumurbaatar B . Increased incidence of aflatoxin B1-induced liver tumors in hepatitis virus C transgenic mice. Int J Cancer. 2011; 130(6):1347-56. PMC: 3161148. DOI: 10.1002/ijc.26140. View

16.

Lu J, Yang W, Lin Y, Jin S, Yuh C . Hepatitis B virus X antigen and aflatoxin B1 synergistically cause hepatitis, steatosis and liver hyperplasia in transgenic zebrafish. Acta Histochem. 2013; 115(7):728-39. DOI: 10.1016/j.acthis.2013.02.012. View

17.

Langouet S, Coles B, Morel F, Becquemont L, Beaune P, Guengerich F . Inhibition of CYP1A2 and CYP3A4 by oltipraz results in reduction of aflatoxin B1 metabolism in human hepatocytes in primary culture. Cancer Res. 1995; 55(23):5574-9. View

18.

Xing Y, Yan J, Niu Y . PXR: a center of transcriptional regulation in cancer. Acta Pharm Sin B. 2020; 10(2):197-206. PMC: 7016272. DOI: 10.1016/j.apsb.2019.06.012. View

19.

Schmidt-Arras D, Rose-John S . IL-6 pathway in the liver: From physiopathology to therapy. J Hepatol. 2016; 64(6):1403-15. DOI: 10.1016/j.jhep.2016.02.004. View

20.

Madden C, Finegold M, Slagle B . Altered DNA mutation spectrum in aflatoxin b1-treated transgenic mice that express the hepatitis B virus x protein. J Virol. 2002; 76(22):11770-4. PMC: 136763. DOI: 10.1128/jvi.76.22.11770-11774.2002. View