Nuclear Met regulates liver cancer metastasis via NF-κB/MMP2 pathway

Abstract

Met is a surface receptor tyrosine kinase which upon hepatocyte growth factor induction, triggers a diversity of downstream signaling cascades that modulates different cellular processes. Emerging evidence has shown the presence of nuclear Met (nMet) in some cancerous tissues and cell lines, postulating that nMet could have unexplored functions within nucleus. Although Met is well known of its oncogenic role in hepatocellular carcinoma (HCC), existence and functions of nMet in HCC are yet to be reported. Our present study aims to examine the clinical association and functions of nMet in HCC. Immunohistochemistry of 103 human HCC paired samples showed that nMet was overexpressed in nearly 90 % of cases. We also found that nMet overexpression was progressively increased along HCC development, from non-tumorous liver tissue to early and advanced HCC. Nonetheless, nMet overexpression was significantly associated with venous invasion and poorer overall survival in HCC patients. As revealed by immunoblot and immunofluorescence, we found that nMet is about 48 kDa and comprises cytoplasmic domain of Met, as it can only be detected by an antibody against the carboxyl terminal of Met. To study the functions of nMet, we employed a lentiviral based inducible exression system to express the cytoplasmic region of Met. In vitro functional assay showed that nMet significantly promoted HCC cell proliferation and anchorage independent growth. It also significantly augmented HCC cell migration and invasiveness. Besides that, nMet also enhanced HCC tumor formation in animal model. Furthermore, we showed that nMet promoted tumor invasiveness and aggressiveness through NF-jB/MMP2 pathway.