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

doi:10.1016/j.tranon.2018.10.010

High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype

Transl Oncol. 2019 Feb;12(2):256-268. doi: 10.1016/j.tranon.2018.10.010. Epub 2018 Nov 12.

Authors

Nicole Golob-Schwarzl¹, Kira Bettermann², Anita Kuldeep Mehta³, Sonja M Kessler⁴, Julia Unterluggauer², Stefanie Krassnig², Kensuke Kojima⁵, Xintong Chen⁵, Yujin Hoshida⁵, Nabeel M Bardeesy⁶, Heimo Müller², Vendula Svendova⁷, Michael G Schimek⁷, Clemens Diwoky⁸, Alexandra Lipfert⁹, Vineet Mahajan², Cornelia Stumptner², Andrea Thüringer², Leopold F Fröhlich¹⁰, Tatjana Stojakovic¹¹, K P R Nilsson¹², Thomas Kolbe¹³, Thomas Rülicke¹⁴, Thomas M Magin¹⁵, Pavel Strnad¹⁶, Alexandra K Kiemer¹⁷, Richard Moriggl¹⁸, Johannes Haybaeck¹⁹

Affiliations

¹ Institute of Pathology, Medical University of Graz, Graz, Austria; Center for Biomarker Research in Medicine, Graz, Austria.
² Institute of Pathology, Medical University of Graz, Graz, Austria.
³ Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
⁴ Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
⁵ Liver Tumor Translational Research Program, University of Texas Southwestern Medical Center, Dallas, USA.
⁶ Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
⁷ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
⁸ Institute of Medical Engineering, Graz University of Technology, Graz, Austria; Institute of Molecular Biosciences, University of Graz, Graz, Austria.
⁹ Institute of Medical Engineering, Graz University of Technology, Graz, Austria.
¹⁰ Institute of Pathology, Medical University of Graz, Graz, Austria; AG VABOS, Department of Cranio-Maxillofacial Surgery, Univerity of Muenster, Germany.
¹¹ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
¹² Department of Chemistry, Linköping University, Linköping, Sweden.
¹³ Biomodels Austria (Biat), University of Veterinary Medicine Vienna, Vienna, Austria; Department IFA-Tulln, University for Natural Resources and Applied Life Sciences Vienna, Vienna, Austria.
¹⁴ Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
¹⁵ Institute of Biology, University of Leipzig, Leipzig, Germany.
¹⁶ Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
¹⁷ Center for Biomarker Research in Medicine, Graz, Austria.
¹⁸ 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.
¹⁹ 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.

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.

Grants and funding

R01 DK099558/DK/NIDDK NIH HHS/United States