Institute of Pathology, Medical University of Graz, Graz, Austria; Center for Biomarker Research in Medicine, Graz, Austria.
Institute of Pathology, Medical University of Graz, Graz, Austria.
Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
Liver Tumor Translational Research Program, University of Texas Southwestern Medical Center, Dallas, USA.
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
Institute of Medical Engineering, Graz University of Technology, Graz, Austria; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
Institute of Medical Engineering, Graz University of Technology, Graz, Austria.
Institute of Pathology, Medical University of Graz, Graz, Austria; AG VABOS, Department of Cranio-Maxillofacial Surgery, Univerity of Muenster, Germany.
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
Department of Chemistry, Linköping University, Linköping, Sweden.
Biomodels Austria (Biat), University of Veterinary Medicine Vienna, Vienna, Austria; Department IFA-Tulln, University for Natural Resources and Applied Life Sciences Vienna, Vienna, Austria.
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
Institute of Biology, University of Leipzig, Leipzig, Germany.
Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
Center for Biomarker Research in Medicine, Graz, Austria.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Bolzmann Institute of Cancer Research, Vienna, Austria; Medical University Vienna, Vienna, Austria.
Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany. Electronic address: Johannes.haybaeck@med.ovgu.de.
background & 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 termed Mallory-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: We analyzed 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 >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.
