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Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways
Author(s) -
Cheng Jianghong,
Zhong Yanhong,
Chen Shuai,
Sun Yan,
Huang Lantang,
Kang Yujia,
Chen Baozhen,
Chen Gang,
Wang Fengli,
Tian Yingpu,
Liu Wenjie,
Feng GenSheng,
Lu Zhongxian
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700120rr
Subject(s) - cancer research , signal transduction , protein kinase b , stat protein , carcinogenesis , janus kinase , biology , gene knockdown , stat3 , chemistry , microbiology and biotechnology , cancer , cell culture , genetics
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 para ‐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 via regulation of Jak2 and signal transducer and activator of transcription 3 phosphorylation and the expression of downstream genes, such as Bcl‐2 (B‐cell lymphoma 2), c‐Myc , MMP7 (matrix metalloproteinase‐7), and cyclin D1 in vitro and in vivo. 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. FASEB J. 31, 5530–5542 (2017). www.fasebj.org