The role of Thioredoxin Interacting Protein in hepatocellular carcinoma development.

Hepatocellular carcinom is a liver tumour of increasing incidence that usually arises in cirrhotic liver. Oxidative stres-induced hepatocyte injury triggers chronic inflammation and hepatocyte apoptosis. Recent evidences suggests that common stress-activated signaling pathways responsable for the induction of cell motility and invasion.HGF/c-Met signaling is a pathway that is activated in hepatocarcinogenesis. It is known that Heparan Sulphate Proteoglycans (HSPGs) works as a co-receptor for HGF/SF and this interaction is important for signaling. Heparin is a member of the glycosaminoglycan family of carbohydrates, a highly-sulfated and has the highest negative charge density of any known biological molecule. Administration of heparin can be useful for the treatment and prevention of hepatic fibrosis and oxidative stress.We previously showed that heparin inhibits HGF induced cell proliferation, cell invasion and cell motility and further microarray analysis was performed to determine molecular mechanism behind heparin induced HGF-SF/c-Met signaling in HCC. TXNIP was the one of the genes, regulator of oxidative stress, was degulated by heparin and HGF-SF induction.The aim of our study was understanding of the regulation mechanism of HGF and heparin induced TXNIP expression. The relation between heparin induced cmet signalling and TXNIP is described as first time in our study. We showed that TXNIP expression is upregulated with HGF induction, a specific inhibitor to cMET receptor was reversed this effect. Downstream signal transduction proteins such as p42, 44 MAPK which are regulated by cMET, was inhibitted in the same pattern with TXNIP. Heparin induction also increased TXNIP expression. The mechanism underlying heparin induction is the increase of cMET phosphorilation. Also p42, 44 MAPK phosphorilation was incresed via heparin induction. Our data let us to conclude that HGF/cMET signal pathway activation has critical role in controlling TXNIP expression, and this activation increase TXNIP expression via p42, 44 MAPK.We founded that TXNIP expression was higher in cells having mesenchymal like phenotype than cells having epihelial like phenotype. It is known that damages causing by oxidative stress is also high in mezenchymal like cells.In conclusion oxidative stress may result in activation of TXNIP and signal transduction pathways like p42,44 MAPK, which is important for oxidative stress resistancy and cell survival.Key words, TXNIP, Glucose, Heparin, HGF, HCC