Abstract 2055: Overexpression of nuclear met activates NF-κB signaling to promote tumorigenesis and metastasis in hepatocellular carcinoma

Abstract

Abstract Met is a surface receptor tyrosine kinase which upon hepatocyte growth factor (HGF) induction, triggers a diversity of downstream signaling cascades that modulates different cellular processes. Frequently, Met signaling pathway is hijacked in human cancers, resulted in abberant expression and activity. 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. Up to date, therapeutic antibodies and kinase inhibitos that undergoing clinical trial are all targeting Met surface receptor, which in this case exhibit limitation in acting against nMet. Althought 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 aim 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 advanced HCC. Nonetheless, nMet overexpression was significantly associated with venous invasion and poorer overall survival in HCC patients. This suggests that nMet may play a pivotal role in HCC tumorigenesis and metastasis. As revealed by immunoblot and immunofluorescence, we found that nMet is about 48kDa and comprises of cytoplasmic domain of Met, as it can only be detected by an antibody against the carboxyl terminal of Met (C28). To study the functions of nMet, we employed a lentiviral based inducible exression system that tightly controlled by doxycycline to express the cytoplasmic region of Met. Immunofluorescence microscopy showed that juxtamembrane deletion of Met accumulates in the nucleus whereas truncated tyrosine kinase domain accumulates in the cytoplasm, implying a region necessary for nuclear localization of the cytoplasmic fragment. 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 activates NF-κB reporter activity which might enhances the pro-metastatic gene expression to promote tumor invasiveness and aggressiveness. Citation Format: Sze Keong Tey, Edith Yuk Ting Tse, Frankie Chi Fat Ko, Judy Wai Ping Yam. Overexpression of nuclear met activates NF-κB signaling to promote tumorigenesis and metastasis in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2055. doi:10.1158/1538-7445.AM2015-2055