BACKGROUND & AIMS
WAP four-disulfide core domain protein 2 (WFDC2), also known as human epididymis protein 4 (HE4), is a small secretory protein that is highly expressed in fibrosis and human cancers, particularly in the ovaries, lungs, and stomach. However, the role of WFDC2 in carcinogenesis is not fully understood. The present study aimed to investigate the role of WFDC2 in gastric carcinogenesis using preneoplastic metaplasia models.
METHODS
Three spasmolytic polypeptide-expressing metaplasia (SPEM) models were established each in wild-type and Wfdc2-knockout mice, with DMP-777, L635, and high-dose tamoxifen, respectively. To reveal the functional role of WFDC2, we performed transcriptomic analysis with DMP-777-treated gastric corpus specimens.
R ESULTS
Wfdc2-knockout mice exhibited remarkable resistance against oxyntic atrophy, SPEM emergence, and accumulation of M2 type macrophages in all three SPEM models. Transcriptomic analysis revealed that Wfdc2 knockout prevented the upregulation of interleukin-33 (IL33) expression in the injured mucosal region of SPEM models. Notably, supplementation of rWFDC2 induced IL33 production and M2 macrophage polarization, and ultimately promoted SPEM development. Moreover, long-term treatment with rWFDC2 was able to induce SPEM development.
CONCLUSIONS
WFDC2 expressed in response to gastric injury promotes SPEM through the upregulation of IL33 expression. These findings provide novel insights into the role of WFDC2 in gastric carcinogenesis.