High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype12

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 lat...

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Published in:Translational oncology 2018-11, Vol.12 (2), p.256-268
Main Authors: Golob-Schwarzl, Nicole, Bettermann, Kira, Mehta, Anita Kuldeep, Kessler, Sonja M., Unterluggauer, Julia, Krassnig, Stefanie, Kojima, Kensuke, Chen, Xintong, Hoshida, Yujin, Bardeesy, Nabeel M., Müller, Heimo, Svendova, Vendula, Schimek, Michael G., Diwoky, Clemens, Lipfert, Alexandra, Mahajan, Vineet, Stumptner, Cornelia, Thüringer, Andrea, Fröhlich, Leopold F., Stojakovic, Tatjana, Nilsson, K.P.R., Kolbe, Thomas, Rülicke, Thomas, Magin, Thomas M., Strnad, Pavel, Kiemer, Alexandra K., Moriggl, Richard, Haybaeck, Johannes
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Language:English
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Summary: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.
ISSN:1936-5233
DOI:10.1016/j.tranon.2018.10.010