ERK5 IS OVEREXPRESSED IN EXPERIMENTAL LIVER INJURY AND IN HEPATOCELLULAR CARCINOMA (HCC) AND IS MODULATED BY SOLUBLE FACTORS IN HCC CELLS

Background and Aims: The large majority of hepatocellular carcinomas (HCC) arises on a chronically injured liver, underscoring the relationship between changes in stroma and appearance of cancer. ERK5 belongs to the mitogen-activated protein kinase family and regulates proliferation, migration, and angiogenesis. Recent data indicate that ERK5 plays an important role in mitogenesis and motility of macrophages and hepatic myofibroblasts. However, little information is available on the role of this molecule in the biology of HCC. Aim of this study was to investigate the possible role of ERK5 in HCC. Methods: Huh7 and HepG2 were cultured by standard methods. Mice were treated with a single administration of carbon tetrachloride, by gavage. Liver tissue was obtained from HCC and peritumoral areas. Results: Exposure of human HCC cell lines, to EGF rapidly and markedly activated ERK5. In addition, in HepG2, ERK5 was activated by leptin, which is increased in conditions of obesity, a known risk factor for HCC. TGF-b also potently activated ERK5, a finding that may be of particular relevance as TGF-b is a critical regulator of the process of epithelial-mesenchymal transition. Silencing of ERK5 with small interfering RNAs (siRNA) resulted in inhibition of EGF-stimulated cell migration. When HepG2 cells were incubated in hypoxia, a condition which frequently occurs in cancer tissue, migration increased, and was abolished by ERK5 silencing. In vivo, analysis of ERK5 expression in human liver showed increased expression in HCC compared to neighboring cirrhotic tissue, and in both compared to normal tissue. In mice acutely intoxicated with carbon tetrachloride, a model which recapitulates, in a shorter time frame, most of the processes operating in a cirrhotic liver with a predisposition to develop HCC, ERK5 expression was dramatically up-regulated (10- to 15-fold). Conclusions: In HCC cells, ERK5 is activated by several stimuli, including leptin, a novel finding in any cell type, and hypoxia. ERK5 is overexpressed in human HCC and in experimental wound healing. These data indicate that ERK5 may exert a dual regulatory role on a) fibrogenesis; b) hepatocarcinoma.