Bidirectional regulation between TMEFF2 and STAT3 may contribute to Helicobacter pylori-associated gastric carcinogenesis

The transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is a single-pass transmembrane protein, and it is downregulated in human gastric cancer and levels correlate with tumor progression and time of survival. However, the mechanism of its dysregulation in gastric cancer is little known. Here we investigate its regulatory mechanism and the bidirectional regulation between TMEFF2 and STAT3 in gastric carcinogenesis. TMEFF2 expression was decreased after Helicobacter pylori (H. pylori) infection in vivo and in vitro. STAT3 directly binds to the promoter of TMEFF2 and regulates H. pylori-induced TMEFF2 downregulation in normal gastric GES-1 cells and gastric cancer AGS cells. Conversely, TMEFF2 may suppress the phosphorylation of STAT3 and TMEFF2-induced downregulation of STAT3 phosphorylation may depend on SHP-1. A highly inverse correlation between the expression of TMEFF2 and pSTAT3 was also revealed in gastric tissues. We now show the deregulation mechanism of TMEFF2 in gastric carcinogenesis and identify TMEFF2 as a new target gene of STAT3. The phosphorylation of STAT3 may be negatively regulated by TMEFF2, and the bidirectional regulation between TMEFF2 and STAT3 may contribute to H. pylori-associated gastric carcinogenesis.(c) 2014 UICC What's new? Certain tumor suppressors and signaling pathways are dysregulated following infection with Helicobacter pylori, but the molecular mechanisms by which the bacterium induces gastric cancer are not fully understood. Here, expression of TMEFF2, a transmembrane protein previously implicated in human gastric cancer, was found to be decreased in response to H. pylori infection, an effect attributed to H. pylori activation of STAT3. Reduced expression of TMEFF2 was associated with elevated STAT3 phosphorylation. Negative regulation of STAT3 by TMEFF2 likely involves interaction with SHP-1. The findings suggest that bidirectional regulation between TMEFF2 and STAT3 contributes to H. pylori-associated gastric carcinogenesis.