Translational Oncology (Feb 2019)
High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype
- Nicole Golob-Schwarzl,
- Kira Bettermann,
- Anita Kuldeep Mehta,
- Sonja M. Kessler,
- Julia Unterluggauer,
- Stefanie Krassnig,
- Kensuke Kojima,
- Xintong Chen,
- Yujin Hoshida,
- Nabeel M. Bardeesy,
- Heimo Müller,
- Vendula Svendova,
- Michael G. Schimek,
- Clemens Diwoky,
- Alexandra Lipfert,
- Vineet Mahajan,
- Cornelia Stumptner,
- Andrea Thüringer,
- Leopold F. Fröhlich,
- Tatjana Stojakovic,
- K.P.R. Nilsson,
- Thomas Kolbe,
- Thomas Rülicke,
- Thomas M. Magin,
- Pavel Strnad,
- Alexandra K. Kiemer,
- Richard Moriggl,
- Johannes Haybaeck
Affiliations
- Nicole Golob-Schwarzl
- Institute of Pathology, Medical University of Graz, Graz, Austria; Center for Biomarker Research in Medicine, Graz, Austria
- Kira Bettermann
- Institute of Pathology, Medical University of Graz, Graz, Austria
- Anita Kuldeep Mehta
- Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
- Sonja M. Kessler
- Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany
- Julia Unterluggauer
- Institute of Pathology, Medical University of Graz, Graz, Austria
- Stefanie Krassnig
- Institute of Pathology, Medical University of Graz, Graz, Austria
- Kensuke Kojima
- Liver Tumor Translational Research Program, University of Texas Southwestern Medical Center, Dallas, USA
- Xintong Chen
- Liver Tumor Translational Research Program, University of Texas Southwestern Medical Center, Dallas, USA
- Yujin Hoshida
- Liver Tumor Translational Research Program, University of Texas Southwestern Medical Center, Dallas, USA
- Nabeel M. Bardeesy
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, USA
- Heimo Müller
- Institute of Pathology, Medical University of Graz, Graz, Austria
- Vendula Svendova
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
- Michael G. Schimek
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
- Clemens Diwoky
- Institute of Medical Engineering, Graz University of Technology, Graz, Austria; Institute of Molecular Biosciences, University of Graz, Graz, Austria
- Alexandra Lipfert
- Institute of Medical Engineering, Graz University of Technology, Graz, Austria
- Vineet Mahajan
- Institute of Pathology, Medical University of Graz, Graz, Austria
- Cornelia Stumptner
- Institute of Pathology, Medical University of Graz, Graz, Austria
- Andrea Thüringer
- Institute of Pathology, Medical University of Graz, Graz, Austria
- Leopold F. Fröhlich
- Institute of Pathology, Medical University of Graz, Graz, Austria; AG VABOS, Department of Cranio-Maxillofacial Surgery, Univerity of Muenster, Germany
- Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
- K.P.R. Nilsson
- Department of Chemistry, Linköping University, Linköping, Sweden
- Thomas Kolbe
- Biomodels Austria (Biat), University of Veterinary Medicine Vienna, Vienna, Austria; Department IFA-Tulln, University for Natural Resources and Applied Life Sciences Vienna, Vienna, Austria
- Thomas Rülicke
- Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria
- Thomas M. Magin
- Institute of Biology, University of Leipzig, Leipzig, Germany
- Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Alexandra K. Kiemer
- Center for Biomarker Research in Medicine, Graz, Austria
- Richard Moriggl
- 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
- Johannes Haybaeck
- Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Address all correspondence to: Prof. Johannes Haybaeck, MD, PhD, Department of Pathology, Otto-von-Guericke-University Magdeburg, Leipziger Straße 44, D-39120 Magdeburg, Germany.
- Journal volume & issue
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Vol. 12,
no. 2
pp. 256 – 268
Abstract
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.
