Research Papers:

Keratin 18-deficiency results in steatohepatitis and liver tumors in old mice: A model of steatohepatitis-associated liver carcinogenesis

Kira Bettermann, Anita Kuldeep Mehta, Eva M. Hofer, Christina Wohlrab, Nicole Golob-Schwarzl, Vendula Svendova, Michael G. Schimek, Cornelia Stumptner, Andrea Thüringer, Michael R. Speicher, Carolin Lackner, Kurt Zatloukal, Helmut Denk and Johannes Haybaeck _

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Oncotarget. 2016; 7:73309-73322. https://doi.org/10.18632/oncotarget.12325

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Kira Bettermann1,*, Anita Kuldeep Mehta1,*, Eva M. Hofer1, Christina Wohlrab1, Nicole Golob-Schwarzl1, Vendula Svendova2, Michael G. Schimek2, Cornelia Stumptner1, Andrea Thüringer1, Michael R. Speicher3, Carolin Lackner1, Kurt Zatloukal1, Helmut Denk1, Johannes Haybaeck1

1Institute of Pathology, Medical University of Graz, Graz 8036, Austria

2Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz 8036, Austria

3Institute of Human Genetics, Medical University of Graz, Graz 8010, Austria

*These authors contributed equally to this work

Correspondence to:

Johannes Haybaeck, email: [email protected]

Keywords: Steatohepatitis, Keratin 18 deficiency, Liver tumors, Mallory-Denk bodies

Received: July 04, 2016     Accepted: September 19, 2016     Published: September 28, 2016


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.

Results: 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.

Materials and Methods: 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).

Conclusions: 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.

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