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High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype.

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.

SUBMITTER: Golob-Schwarzl N

PROVIDER: S-EPMC6234703 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype.

Golob-Schwarzl Nicole N Bettermann Kira K Mehta Anita Kuldeep AK Kessler Sonja M SM Unterluggauer Julia J Krassnig Stefanie S Kojima Kensuke K Chen Xintong X Hoshida Yujin Y Bardeesy Nabeel M NM Müller Heimo H Svendova Vendula V Schimek Michael G MG Diwoky Clemens C Lipfert Alexandra A Mahajan Vineet V Stumptner Cornelia C Thüringer Andrea A Fröhlich Leopold F LF Stojakovic Tatjana T Nilsson K P R KPR Kolbe Thomas T Rülicke Thomas T Magin Thomas M TM Strnad Pavel P Kiemer Alexandra K AK Moriggl Richard R Haybaeck Johannes J

Translational oncology 20181112 2

<h4>Background & aims</h4>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.<h4>Methods</h4>We analyzed livers of aged Krt18<sup>-/-</sup> mice that spontane ...[more]

PMID: 30439626

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Project description:Alcohol-associated liver fibrosis accumulates over decades, driven by hepatic inflammation and cell death. We investigated the diagnostic accuracy of keratin-18 degradation, measured using serum M30 and M65 levels, and the ActiTest for hepatic inflammatory activity in patients with compensated alcohol-associated liver disease (ALD). Furthermore, we evaluated the prognostic accuracy of markers for liver-related events and all-cause mortality. All findings were compared with routine liver function tests: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase. Our prospective, biopsy-controlled, single-center study included 265 patients with ongoing or prior excessive alcohol intake, representing the full spectrum of compensated ALD. We defined hepatic inflammatory activity as a combined score of lobular inflammation and ballooning. For severe hepatic inflammatory activity (n = 40), we found excellent diagnostic accuracy for M30 (area under the receiver operating characteristics curve [AUROC] = 0.90), M65 (AUROC = 0.86), and AST (AUROC = 0.86). Elevated M30 (M30 > 240 U/L) had the highest positive predictive value (PPV) and specificity, significantly higher than M65, ActiTest and ALT, but not AST (M30: sensitivity = 83%, specificity = 82%, positive predictive value = 45%, negative predictive value = 95%). Patients were followed up for 1445 patient-years. All markers, except for ALT, significantly predicted liver-related events and all-cause mortality. After adjusting for advanced fibrosis, drinking behavior and body mass index, M30 and M65 remained significant predictors of liver-related events, whereas M30 and AST were significant predictors of all-cause mortality. Conclusion: M30 and AST accurately detect severe hepatic inflammatory activity in patients with compensated ALD. M30 was the only significant predictor of both liver-related events and all-cause mortality after adjusting for advanced fibrosis, body mass index, and drinking behavior at inclusion.

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High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype.

Publications

High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype.

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