TY - JOUR
T1 - High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype
AU - Golob-Schwarzl, Nicole
AU - Bettermann, Kira
AU - Mehta, Anita Kuldeep
AU - Kessler, Sonja M.
AU - Unterluggauer, Julia
AU - Krassnig, Stefanie
AU - Kojima, Kensuke
AU - Chen, Xintong
AU - Hoshida, Yujin
AU - Bardeesy, Nabeel M.
AU - Müller, Heimo
AU - Svendova, Vendula
AU - Schimek, Michael G.
AU - Diwoky, Clemens
AU - Lipfert, Alexandra
AU - Mahajan, Vineet
AU - Stumptner, Cornelia
AU - Thüringer, Andrea
AU - Fröhlich, Leopold F.
AU - Stojakovic, Tatjana
AU - Nilsson, K. P.R.
AU - Kolbe, Thomas
AU - Rülicke, Thomas
AU - Magin, Thomas M.
AU - Strnad, Pavel
AU - Kiemer, Alexandra K.
AU - Moriggl, Richard
AU - Haybaeck, Johannes
N1 - Funding Information:
We are thankful to Gerda and Hans Heid for providing K8 and K18 antibodies. We thank Peter Bannasch for providing human tissues. We thank Monika Artl for her help with the CGH analysis. This study was supported by grants of the “Kurt und Senta Herrmann Stiftung” (to M.G.S. and J.H.) and the Austrian Genome Programme GEN-AU (to K.Z. and to T.R.), and R. M. was supported by a private donation from Lichtenstein. Work in the Magin lab was partially supported by the DFG (MA1316-15, MA1316-17, MA1316-19, MA1316-21, INST 268/230-1). This work was supported by the German Research Foundation grant STR 1095/4-2 and Else Kröner Exzellenzstipendium (to P.S.). The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115234, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies (to JH.).
Funding Information:
We are thankful to Gerda and Hans Heid for providing K8 and K18 antibodies. We thank Peter Bannasch for providing human tissues. We thank Monika Artl for her help with the CGH analysis. This study was supported by grants of the “ Kurt und Senta Herrmann Stiftung ” (to M.G.S. and J.H.) and the Austrian Genome Programme GEN-AU (to K.Z. and to T.R.), and R. M. was supported by a private donation from Lichtenstein . Work in the Magin lab was partially supported by the DFG ( MA1316-15 , MA1316-17, MA1316-19 , MA1316-21 , INST 268/230-1 ). This work was supported by the German Research Foundation grant STR 1095/4-2 and Else Kröner Exzellenzstipendium (to P.S.). The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115234 , resources of which are composed of financial contribution from the European Union's Seventh Framework Programme ( FP7/2007-2013 ) and EFPIA companies (to JH.).
Publisher Copyright:
© 2018 The Authors
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
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U2 - 10.1016/j.tranon.2018.10.010
DO - 10.1016/j.tranon.2018.10.010
M3 - Article
C2 - 30439626
AN - SCOPUS:85056230680
VL - 12
SP - 256
EP - 268
JO - Translational Oncology
JF - Translational Oncology
SN - 1936-5233
IS - 2
ER -