Background & Aims: WAP 4-disulfide core domain protein 2 (WFDC2), also known as human epididymis protein 4, 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 with the use of preneoplastic metaplasia models. Methods: Three spasmolytic polypeptide–expressing metaplasia (SPEM) models were established in both 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. Results: Wfdc2-knockout mice exhibited remarkable resistance against oxyntic atrophy, SPEM emergence, and accumulation of M2-type macrophages in all 3 SPEM models. Transcriptomic analysis revealed that Wfdc2-knockout prevented the up-regulation of interleukin-33 (IL33) expression in the injured mucosal region of SPEM models. Notably, supplementation of recombinant WFDC2 induced IL33 production and M2 macrophage polarization, and ultimately promoted SPEM development. Moreover, long-term treatment with recombinant WFDC2 was able to induce SPEM development. Conclusions: WFDC2 expressed in response to gastric injury promotes SPEM through the up-regulation of IL33 expression. These findings provide novel insights into the role of WFDC2 in gastric carcinogenesis.
Bibliographical noteFunding Information:
Funding This project was supported by the Korea Mouse Phenotyping Project (NRF-2016M3A9D5A01952416), the Ministry of Food and Drug Safety (14182MFDS978), and the Brain Korea 21 PLUS Project for Medical Science at Yonsei University . K.M.L. is supported by a grant from the National Research Foundation , South Korea, funded by the Ministry of Science and ICT (2018R1A5A2025286). J.R.G. is supported by grants from a Department of Veterans Affairs Merit Review Award (IBX000930) and the National Institutes of Health (R01 DK101332).
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- Interleukin-33 (IL33)
- M2 macrophage