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 - Publisher Copyright:
© 2018 The Authors
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
SN - 1944-7124
VL - 12
SP - 256
EP - 268
JO - Translational Oncology
JF - Translational Oncology
IS - 2
ER -