The role of the interaction Between Hepatocyte Growth Factor/c-Met Pathway and Mucin1 and Mucin20 in the Development of Hepatocellular Carcinoma

Mucin1 and 20 are high molecular weight transmembrane glycoproteins that are expressed by different cell types which have protective effects on the cell surface and on the other hand act as cell surface receptors and sensors. Transmembrane mucins are thought to have roles in the regulation of differantiation, proliferation and metastasis of cells. Since the cytoplasmic domains of transmembrane mucins interact with various proteins in signal transduction pathways, it is thought that they might have association with hepatocyte growth factor receptor, c-Met. The mRNA expression levels of transmembrane Mucin1, Mucin20 and c-Met were investigated in hepatocellular carcinoma cell lines with reverse transcriptase polymerase chain reaction and the protein expression levels of Mucin1 and c-Met were investigated with western blot analysis. Besides, Mucin1 and c-Met expression discrepancies were analyzed in paraffin embedded tissue samples of normal, cirrosis and hepatocellular carcinoma by immunohistochemistry. While there was no Mucin1 expression in well differentiated epithelial cell lines Huh-7, Hep3B and HepG2, poorly differentiated mesenchymal cell lines Snu-398, Snu-449, Snu-475, Mahlavu and SK-Hep1 had Mucin1 expression. It was also determined that c-Met-Mucin1 and beta catenin-Mucin1 co-immunoprecipitate under hepatocyte growth factor induction in Mahlavu cell line which has high Mucin1 and c-Met expression in protein level. These physical associations decreased in a time dependent manner under hepatocyte growth factor induction. Besides, phosphorilated S552 beta catenin levels were also affected by hepatocyte growth factor and decreased time dependently. There was no Mucin1 and c-Met expression in normal liver tissues. Mucin1 and c-Met expression rates in cirrhosis were 15% and 89% and p values were 0.089 and 0.001, respectively. In hepatocellular carcinoma tissues while Mucin1 expression increased to 45%, c-Met expression rate was 88% (p=0.001). Mucin1 expression rate in well differentiated hepatocellular carcinomas were lower than moderate and poorly differentiated ones. A statistically significant elevation was obtained in cytoplasmic c-Met in moderate and poorly differentiated hepatocellular carcinomas compared to well differentiated samples (p=0.001).In conclusion, these data suggest that Mucin1 overexpression is important in transitition from cirrhosis to hepatocellular carcinoma while increase in c-Met expression may have importance in the development of cirrhosis.