Signaling pathways involved in carcinogenesis in a double hit mouse model of cholangiopathy and hepatitis B virus

T Matono; Y Churin; H Reinhard; M Roderfeld; D Schröder; D Zahner; D Glebe; E Roeb

doi:10.1055/s-0033-1361052

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

Signaling pathways involved in carcinogenesis in a double hit mouse model of cholangiopathy and hepatitis B virus

T Matono ¹, Y Churin ¹, H Reinhard ¹, M Roderfeld ¹, D Schröder ¹, D Zahner ², D Glebe ³, E Roeb ¹

¹Justus-Liebig-Universität Gießen, Gastroenterologie, Medizinische Klinik II, Gießen, Germany
²Justus-Liebig-Universität Gießen, Zentrales Tierlabor, Gießen, Germany
³Justus-Liebig-Universität Gießen, Institut für Medizinische Virologie, Gießen, Gießen

Abstract

Background and aim: Primary sclerosing cholangitis (PSC) is one of the most famous liver cholestatic diseases, which leads to liver cirrhosis and liver failure. Hepatitis B virus (HBV) also leads to liver cirrhosis and hepatocellular carcinoma (HCC). Abcb4 knock out (Abcb4-/-) mice are known to develop cholangiopathy represented by portal tract inflammation and a severe ductal proliferation and developed nodules and HCC. Also, HBV transgenic mice (HBV+/-), which show liver specific expression of the large envelope polypeptide of human HBV, lead to liver damage and HCC. We already reported that these mice lead to liver inflammation and fibrosis. The aim of the present study is to clarify the signaling pathways involved in carcinogenesis in one-year old Abcb4-/-/HBV+/- hybrid mice.

Methods: Abcb4-/-/HBV+/-mice were raised by crossing Abcb4-/- with HBV+/- on BALB/c background. We performed serum analysis, hydroxyproline measurement, qRT-PCR, and Western blots.

Results: The rate and size of HCC in HBV+/- and Abcb4-/-/HBV+/- are higher than those of super controls (WT) andAbcb4-/- mice. Serum ALT levels in Abcb4-/-, HBV+/- and Abcb4-/-/HBV+/- mice are significantly higher than in WT. Hydroxyproline, Collagen1 and TIMP-1-transcription in Abcb4-/- and Abcb4-/-/HBV+/- mice are higher than in WT and HBV+/-. Phospho(P)-JNK, P-cJun and P-STAT3 in Abcb4-/-/HBV+/- are increased in comparison to controls.

Conclusion: Double injuryin combined Abcb4-/- and HBV+/-mice resulted in raised inflammation, fibrosis and signaling pathways which seem to be involved in enhanced carcinogenesis. The new mouse model might be a valuable tool to study immunologic mechanisms of human HBV associated cholangitis and associated complications.