Abstract A38: Steatohepatitis-associated hepatocellular carcinoma: Evidence of a keratin-based disease.

Background: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, hepatocyte ballooning and cytoplasmic protein aggregates termed Mallory-Denk bodies (MDBs). MDBs are generally composed of misfolded keratin (K) 8, 18 and in part p62 and ubiquitin. It is well established that K aggregates are critical for MDB formation, thus Ks are associated with SH which is one of the main preconditions for the development of liver cirrhosis and hepatocellular carcinoma (HCC). Aims: In this study we aimed to clarify the cellular and molecular mechanisms of relative K8 excess over K18 on hepatocarcinogenesis in mice and its functional and clinical implication in human alcoholic and non-alcoholic SH (ASH/NASH)-induced liver cancer. Methods: 18 month-old krt18-deficient (krt18-/-129P2/OlaHsd background) mice were investigated for the incidence of SH and SH-induced liver tumors by radiology, macroscopy, histology, immunohistochemistry, gene expression, lipidome analysis, and immunoblotting. Results: Aged krt18-/- mice developed the entire morphological spectrum of SH whereas aged wild-type (wt) mice showed simple steatosis. Aminotransaminase levels were also elevated in aged krt18-/- mice. Interestingly, 64% of male and 25% of female 18 month-old krt18-/- mice developed liver tumors revealing morphological and genetic features of HCC whereas 45% of male and 16% of female krt18+/- mice and 42% of wt mice developed HCC. Conclusion: Aged krt18-/- mice represent a novel spontaneous SH and SH associated HCC model with significant gender differences revealing features related to human HCC. Therefore, variations of hepatocellular K18 seem to have an effect on the susceptibility regarding SH and SH-induced HCC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A38. Citation Format: Anita Kuldeep Mehta, Kira Bettermann, Eva M. Lederer, Christina Ernst, Sonja M. Kessler, Kensuke Kojima, Xintong Chen, Yujin Hoshida, Bryan C. Fuchs, Vendula Svendova, Michael G. Schimek, Monika Mach, Michael R. Speicher, Tatjana Stojakovic, Thomas M. Magin, Pavel Strnad, Michael Trauner, Alexandra K. Kiemer, Snorri S. Thorgeirsson, Michael Karin, Josep M. Llovet, Kurt Zatloukal, Helmut Denk, Carolin Lackner, Johannes Haybaeck. Steatohepatitis-associated hepatocellular carcinoma: Evidence of a keratin-based disease. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A38.