Keratin 18-deficiency results in steatohepatitis and liver tumors in old mice: A model of steatohepatitis-associated liver carcinogenesis.
Backround: Steatohepatitis (SH)-associated liver carcinogenesis is an increasingly important issue in clinical medicine. SH is morphologically characterized by steatosis, hepatocyte injury, ballooning, hepatocytic cytoplasmic inclusions termed Mallory-Denk bodies (MDBs), inflammation and fibrosis.



17-20-months-old Krt18-/- and Krt18+/- mice in contrast to wt mice spontaneously developed liver lesions closely resembling the morphological spectrum of human SH as well as liver tumors. The pathologic alterations were more pronounced in Krt18-/- than in Krt18+/- mice. The frequency of liver tumors with male predominance was significantly higher in Krt18-/- compared to age-matched Krt18+/- and wt mice. Krt18-deficient tumors in contrast to wt animals displayed SH features and often pleomorphic morphology. aCGH analysis of tumors revealed chromosomal aberrations in Krt18-/- liver tumors, affecting loci of oncogenes and tumor suppressor genes.



Livers of 3-, 6-, 12- and 17-20-months-old aged wild type (wt), Krt18+/- and Krt18-/- (129P2/OlaHsd background) mice were analyzed by light and immunofluorescence microscopy as well as immunohistochemistry. Liver tumors arising in aged mice were analyzed by array comparative genomic hybridization (aCGH).



Our findings show that K18 deficiency of hepatocytes leads to steatosis, increasing with age, and finally to SH. K18 deficiency and age promote liver tumor development in mice, frequently on the basis of chromosomal instability, resembling human HCC with stemness features.
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Kira
K
Bettermann
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Anita Kuldeep
AK
Mehta
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Eva M
EM
Hofer
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Christina
C
Wohlrab
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Nicole
N
Golob-Schwarzl
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz 8036, Austria.
Vendula
V
Svendova
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz 8036, Austria.
Michael G
MG
Schimek
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Cornelia
C
Stumptner
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Andrea
A
Thüringer
Institute of Human Genetics, Medical University of Graz, Graz 8010, Austria.
Michael R
MR
Speicher
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Carolin
C
Lackner
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Kurt
K
Zatloukal
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Helmut
H
Denk
Institute of Pathology, Medical University of Graz, Graz 8036, Austria.
Johannes
J
Haybaeck
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications* / Q000235:genetics*; D023281:Genomics / Q000379:methods; D007150:Immunohistochemistry; D053538:Keratin-18 / Q000172:deficiency / Q000235:genetics*; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
D053538:Keratin-18
Mallory-Denk bodies; keratin 18 deficiency; liver tumors; steatohepatitis
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