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.