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.

Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high‐fat diet in the genetically diverse Collaborative Cross mouse model

“…This indicates that analysis of the expression of fibrosis marker genes can be used for monitoring the progression of NAFL to NASH. Similar results of early upregulation fibrosis marker genes, including Col1a1 and Tnf , and a high Krt8/Krt18 ratio were observed in a diet‐induced mouse model of hepatic fibrosis 18 and in a Krt18 −/− transgenic mouse model of NASH 31 …”

KRT18 is correlated with the malignant status and acts as an oncogene in colorectal cancer

“…In addition, KRT18 expression had 4.6-times increase in high metastatic lung cancer cell line compared with low metastatic lung cancer cell line [26]. In hepatocellular carcinoma patients, levels of KRT18 expression were positively correlated with lymph node metastasis and aggressive phenotype [27,28]. Moreover, Afrem et al [29] reported KRT18 overexpression was correlated with advanced clinical stage, poor differentiation, and high invasion pattern in oral squamous cell carcinoma patients.…”

Homeostasis of Glucose and Lipid in Non-Alcoholic Fatty Liver Disease

“…Furthermore, particular stains such as cytoplasmic keratin (KRT) 8/18 immunohistochemistry may detect ballooned hepatocytes. A recent study by Golob-Schwarzl et al [8] found that a high KRT8/18 ratio caused the change in hepatic lipid profile resulting in ballooning with a Mallory–Denk body (MDB) formation. Numerous risk factors, such as metabolic derangement, obesity, and insulin resistance (IR) lead to liver accumulation of triglycerides and free fatty acids and growing of NAFLD [9].…”