期刊
FEBS JOURNAL
卷 289, 期 15, 页码 4536-4548出版社
WILEY
DOI: 10.1111/febs.16403
关键词
Foxd3; Gab2; hepatocellular carcinoma
资金
- National Key R&D Program of China [2018YFC1003701, 2017YFC1001402]
- National Natural Science Foundation of China [31970797, 31671564]
This study identifies a mutual inhibition between the tumor suppressor Foxd3 and the tumor enhancer Gab2 in hepatocellular carcinoma. Foxd3 inhibits the expression of Gab2 and its associated cell proliferation and migration, providing a potential therapeutic target for liver cancer.
Our previous study demonstrated that GAB2 promoted tumorigenesis in liver tissue and was a potential target for the treatment of hepatocellular carcinoma (HCC). Here, we identified that the tumour suppressor protein Forkhead box D3 (Foxd3) is a transcriptional repressor of the Gab2 gene. In human HCC cells, FOXD3 expression is low, but GAB2 expression is abundant. Increased Foxd3 expression inhibited the expression of Gab2 in a dose-dependent manner. Ectopic expression of Foxd3 in HCC cells reduced Gab2-mediated promotion of cell proliferation and migration in vitro. Foxd3 also inhibited Gab2-stimulated phosphorylation of Jak2 and Stat3. Furthermore, the protein levels of Foxd3 and Gab2 had a clear negative correlation: Gab2 expression was induced, whereas Foxd3 expression was suppressed in most tumour tissues in mice with diethylnitrosamine (DEN)-induced hepatocellular carcinoma. These results suggest that the tumour suppressor Foxd3 and tumour enhancer Gab2 mutually inhibit each other to synergistically control the occurrence of HCC, providing a novel mechanism for treating this disease.
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