HEPATOCYTE-SPECIFIC LYMPHOTOXIN EXPRESSION CAUSES CHRONIC HEPATITIS INDUCED HEPATOCELLULAR CARCINOMA IN TNFR1 super(-/-) BUT NOT IN RAG1 super(-/-) OR IKK beta super( Delta HEP) MICE

• Published in: Anticancer research Vol. 28; no. 5C
• Main Authors: Haybaeck, J, Heikenwalder, M, Zeller, N, Wolf, MJ, Bremer, J, Weber, A, Kurrer, M, Wagner, U, Kopf, M, Karin, M, Aguzzi, A
• Format: Journal Article
• Language: English
• Published: 01.10.2008
• ISSN: 0250-7005

Hepatocellular carcinoma (HCC), the most common liver cancer, is mainly induced by chronic hepatitis. Lymphotoxin (LT alpha beta ) was recently demonstrated to be up-regulated in livers of patients suffering from virus-induced hepatitis and HCC. We generated transgenic mice with liver-specific expression of LT alpha beta (AlbLT alpha beta ). Characteristic morphological features of chronic portal and lobular hepatitis were detected in livers from transgenic mice at the age of 6-9 months, preceded by hepatocyte-specific expression of chemokines (e.g. IP10, CXCL1, CCL2). Elevated serum levels of aminotransferases starting from 8 weeks of age indicated liver damage in AlbLTaP mice. Remarkably, at an age of greater than or equal to 300 days, 30% of transgenic mice developed HCCs. Hepatitis and HCC genesis was fully prevented in AlbLT alpha beta mice backcrossed to rag1 super(-/-)and IKK beta super( Delta hep) mice. In contrast, tnfr1 super(-/-) mice developed hepatitis and HCC. Here, we describe a new model of chronic hepatitis-induced HCC. Transcriptome analysis at various stages of hepatitis and HCC development reveals many similarities to virus-induced hepatitis and HCC in humans and enables us to dissect signalling events in AlbLT alpha beta , AlbLT alpha beta x Ikk beta super( Delta hep) and AlbLT alpha beta x tnfr1 super(-/-) mice. Therefore, LT alpha beta expression by hepatocytes suffices to induce chronic hepatitis causing HCC in a lymphocyte- and IKK beta -dependent, but TNFR1-independent manner, rather than directly acting as an oncogene.