Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Mehta, A.
Keratin 18-deficiency results in steatohepatitis and liver tumor formation in aged mice: A novel model of steatohepatitis-associated liver carcinogenesis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Haybäck Johannes
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- Abstract:
- Hepatocellular carcinoma (HCC) is among the most lethal cancers with very poor prognosis and the third most frequent aggressive hepatocyte driven tumor. Besides virus-induced HCC, steatohepatitis (SH)-driven liver tumorigenesis is becoming increasingly important in clinical medicine. SH which is a disease with fatty liver, ballooning of hepatocytes, occurrence of protein aggregates termed Mallory-Denk bodies (MDBs), fibrosis and inflammation is becoming more prevalent in recent years. Depending on the inducing factors it occurs as alcoholic or non-alcoholic steatohepatitis (ASH/NASH) or non-alcoholic fatty liver disease (NAFLD). SH is currently affecting approximately 3% of the world population. It is believed that the fatal progression of NASH to cirrhosis and HCC, depends on pathological lipid metabolism and oxidative stress. Several lines of evidence indicate the existence of susceptibility and modifier genes that synergize with lifestyle factors causing NAFLD. However, the individual risk of obese people to develop HCC depends on largely unknown determinants. Certain features of SH can be reproduced in animal models by a variety of treatments. This work demonstrates the pathophysiological and molecular mechanisms of relative K8 excess over K18 on hepatocarcinogenesis in mice and its functional and clinical implication in human ASH/NASH-induced liver cancer. Livers of aged (17 to 20 month-old) wild type (wt), keratin (Krt)18+/- and Krt18-/- (129P2/OlaHsd background) mice were analyzed by light and immunofluorescence microscopy, immunohistochemistry, comparative genomic hybridization arrays (aCGH) and quantitative reverse transcriptase polymerase chain reaction (qPCR) for liver cell injury and tumor development. Moreover, hepatic levels of fatty acids (FA) were determined and their composition was analyzed by gas chromatography coupled with mass spectrometry (GC-MS). 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 mice 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. aCGH-analysis of wt, Krt18+/- and Krt18-/- tumors revealed different patterns of chromosomal aberrations; most aberrations were found in Krt18-/- liver tumors, affecting loci of oncogenes, tumor suppressor and liver cancer-associated Up regulated (PYCARD, RUNX3, CXCR4, CCL5, BAX, SOCS1, SOCS3 and TLR4) and down regulated (BIRC5, PTEN, NF¿B1, CASP8, TP53, VEGFA, CCND1, MYC, IGFBP1, IGF2) genes. Taken together, our finding reinforces the notion that a high KRT 8/18-ratio is associated with SH and SH-driven HCC. The excess of K8 as inducer of protein-aggregation in liver, which leads to a dysbalanced hepatic homeostasis, can be suggested as causally important based on the data presented here. Krt18-/- mice therefore represent a novel spontaneous SH-associated HCC-model. Variants of hepatocellular K18 seem to have an effect on the susceptibility towards SH-induced HCC. This study highlights that keratins do not only provide mechanical properties to the cell but also fulfill non-mechanical functions. These play an important role under pathological conditions and causally link keratins with SH and HCC.