FOXD3 and GAB2 as a pair of rivals antagonistically control hepatocellular carcinogenesis

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. Foxd3 was identified as a transcriptional repressor of Gab2. In HCC cells, FOXD3 expression is low but GAB2 expression is abundant. Gab2 expression was induced, whereas Foxd3 expression was suppressed in most tumour tissues in mice with diethylnitrosamine (DEN)‐induced hepatocellular carcinoma, suggesting 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.