1. High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype12
- Author
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Johannes Haybaeck, Kensuke Kojima, Thomas Kolbe, Nicole Golob-Schwarzl, Vendula Svendova, Yujin Hoshida, Heimo Müller, Alexandra K. Kiemer, Michael G. Schimek, Stefanie Krassnig, Julia Judith Unterluggauer, Thomas M. Magin, Thomas Rülicke, Vineet Mahajan, Richard Moriggl, Kira Bettermann, Anita K. Mehta, Alexandra Lipfert, Andrea Thüringer, Cornelia Stumptner, K.P.R. Nilsson, Tatjana Stojakovic, Leopold F. Fröhlich, Sonja M. Kessler, Nabeel Bardeesy, Clemens Diwoky, Pavel Strnad, and Xintong Chen
- Subjects
0301 basic medicine ,Cancer Research ,Original article ,Cell- och molekylärbiologi ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Keratin ,medicine ,Intermediate filament ,chemistry.chemical_classification ,Erratum/Corrigendum ,Chemistry ,Liver cell ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,Keratin 8 ,Steatohepatitis ,Steatosis ,Cell and Molecular Biology - Abstract
BACKGROUND amp; AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termedMallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: Weanalyzed livers of aged Krt18(-/-) mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18(-/-) mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS: Our analysis of the genetic profile of Krt18(-/-) mice with 26 human hepatoma cell lines and with data sets of amp;gt;300 patients with HCC, where Krt18(-/-) gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS: We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC. Funding Agencies|Kurt und Senta Herrmann Stiftung; Austrian Genome Programme GEN-AU; DFG [MA1316-15, MA1316-17, MA1316-19, MA1316-21, INST 268/230-1]; German Research Foundation [STR 1095/4-2]; Else Kroner Exzellenzstipendium; Innovative Medicines Initiative Joint Undertaking from the European Unions Seventh Framework Programme (FP7/2007-2013) [115234]; EFPIA companies
- Published
- 2018