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 StojakovicK. P.R. Nilsson, Thomas Kolbe, Thomas Rülicke, Thomas M. Magin, Pavel Strnad, Alexandra K. Kiemer, Richard Moriggl, Johannes Haybaeck

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)256-268
Number of pages13
JournalTranslational Oncology
Volume12
Issue number2
DOIs
StatePublished - Feb 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Golob-Schwarzl, N., Bettermann, K., Mehta, A. K., Kessler, S. M., Unterluggauer, J., Krassnig, S., Kojima, K., Chen, X., Hoshida, Y., Bardeesy, N. M., Müller, H., Svendova, V., Schimek, M. G., Diwoky, C., Lipfert, A., Mahajan, V., Stumptner, C., Thüringer, A., Fröhlich, L. F., ... Haybaeck, J. (2019). High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype. Translational Oncology, 12(2), 256-268. https://doi.org/10.1016/j.tranon.2018.10.010