Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways

Abstract

Our previous studies have found that Growth factor receptor-bound protein 2-associated binding protein 2 (Gab2)-a docking protein-governs the development of fatty liver disease. Here, we further demonstrate that Gab2 mediates hepatocarcinogenesis. Compared with a faint expression in <i>para</i>-carcinoma tissue, Gab2 was highly expressed in ∼60-70% of human hepatocellular carcinoma (HCC) specimens. Deletion of Gab2 dramatically suppressed diethylnitrosamine-induced HCC in mice. The oncogenic effects of Gab2 in HepG2 cells were promoted by Gab2 overexpression but were rescued by Gab2 knockdown. Furthermore, Gab2 knockout in HepG2 cells restrained cell proliferation, migration and tumor growth in nude mice. Signaling pathway analysis with protein kinase inhibitors demonstrated that oncogenic regulation by Gab2 in hepatic cells involved multiple signaling molecules, including ERK, Akt, and Janus kinases (Jaks), especially those that mediate inflammatory signaling. IL-6 signaling was increased by Gab2 overexpression and impaired by Gab2 deletion <i>via</i> regulation of Jak2 and signal transducer and activator of transcription 3 phosphorylation and the expression of downstream genes, such as <i>Bcl-2</i> (B-cell lymphoma 2), <i>c-Myc</i>, <i>MMP7</i> (matrix metalloproteinase-7), and <i>cyclin D1</i><i>in vitro</i> and <i>in vivo</i> These data indicate that Gab2 mediates the pathologic progression of HCC by integrating multiple signaling pathways and suggest that Gab2 might be a powerful therapeutic target for HCC.-Cheng, J., Zhong, Y., Chen, S., Sun, Y., Huang, L., Kang, Y., Chen, B., Chen, G., Wang, F., Tian, Y., Liu, W., Feng, G.-S., Lu, Z. Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways.