Interaction between FOXO1 and human epidermal growth factor receptor 2/neu regulates gastric tumor growth and metastasis

Abstract

Background: The biological significance of FOXO1, a member of the forkhead box O transcription factor family, in gastric cancer (GC) remains unclear. The present study provides direct evidence of the role of FOXO1 in tumor growth and metastasis of GC in relation to human epidermal growth factor receptor 2 (HER2).

Methods: The expressions of FOXO1 and HER2 were modulated in GC cell lines (SNU-638, MKN45, SNU-216 and NCI-N87) by stable transfections of their shRNAs or gene construct. The modulation effects of FOXO1 and HER2 expression on GC phenotypes were evaluated in vitro and in animal models. In addition, correlation between the expression of FOXO1 and HER2 was analysed in GC clinical specimens, cell lines and xenografts.

Results: FOXO1 silencing in GC cells increased colony formation and mesenchymal transition in vitro as well as tumor growth and metastasis in nude mice, whereas HER2 silencing induced the opposite results. Furthermore, an inverse relationship between FOXO1 and HER2 was found in clinical specimens of GC, GC cells and GC xenograft tumors. Although a negative crosstalk between these two molecules was shown, double knockdown of both FOXO1 and HER2 in GC cells revealed that HER2 silencing reversed the FOXO1 shRNA-induced migration and invasion even without the FOXO1 restoration.

Conclusions: My results indicate that loss of FOXO1 promotes GC growth and metastasis through upregulating HER2 expression and that the HER2 expression is more critical to the induction of GC cell metastasis. The present study provides evidence that the FOXO1/HER2 pathway may regulate GC progression in a subgroup of GC patients.