Abstract
Understanding of the pathophysiology of cholestasis associated carcinogenesis could challenge the development of new personalized therapeutic approaches and thus improve prognosis. Simultaneous damage might aggravate hepatic injury, induce chronic liver disease and even promote carcinogenesis. We aimed to study the effect of Hepatitis B virus surface protein (HBsAg) on cholestatic liver disease and associated carcinogenesis in a mouse model combining both impairments. Hybrids of Abcb4−/− and HBsAg transgenic mice were bred on fibrosis susceptible background BALB/c. Liver injury, serum bile acid concentration, hepatic fibrosis, and carcinogenesis were enhanced by the combination of simultaneous damage in line with activation of c-Jun N-terminal kinase (JNK), proto-oncogene c-Jun, and Signal transducer and activator of transcription 3 (STAT3). Activation of Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) and Eukaryotic translation initiation factor 2A (eIF2α) indicated unfolded protein response (UPR) in HBsAg-expressing mice and even in Abcb4−/− without HBsAg-expression. CONCLUSION: Cholestasis-induced STAT3- and JNK-pathways may predispose HBsAg-associated tumorigenesis. Since STAT3- and JNK-activation are well characterized critical regulators for tumor promotion, the potentiation of their activation in hybrids suggests an additive mechanism enhancing tumor incidence.
Highlights
Various phenotypes of chronic liver disease like progressive familial intrahepatic cholestasis (PFIC type 3) or biliary liver cirrhosis have been attributed to mutations of the human ABCB4 gene [1]
We aimed to study the effect of Hepatitis B virus surface protein (HBsAg) on cholestatic liver disease and associated carcinogenesis in a mouse model combining both impairments
The extent of liver damage, cholestasis, and fibrosis was enhanced in Abcb4-/-/HBsAg+/- mice
Summary
Various phenotypes of chronic liver disease like progressive familial intrahepatic cholestasis (PFIC type 3) or biliary liver cirrhosis have been attributed to mutations of the human ABCB4 gene [1]. Hepatic injury in patients with chronic hepatitis B virus (HBV) infection has mainly been attributed to T cell response against infected hepatocytes [4, 5]. Www.impactjournals.com/oncotarget observations in HBV infected patients under conditions of immune suppression and in transgenic mouse models of HBV infection suggest, that cellular modifications induced by HBsAg proteins may lead to liver disease in the absence of adaptive immune responses [6,7,8]. Transgenic mice expressing HBV surface proteins demonstrated comparable histopathologic pattern including inflammation, regenerative hyperplasia, transcriptional deregulation, aneuploidy progressing to neoplasia, and even hepatocellular carcinoma (HCC) [6, 9,10,11]. Trierweiler et al demonstrated that the transcription factor c-JUN/AP-1 promotes HCC in HBsAg-transgenic mice [18]
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