Haengdueng Jeong1, Buhyun Lee1, Kwang H Kim1, Soo Young Cho2, Yejin Cho1, Jeongeun Park3, Yura Lee1, Yeseul Oh1, Bo Ram Hwang4, Ah-Ra Jang5, Jong-Hwan Park5, Ji-Ho Park6, Sang-Ho Jeong6, Daekee Lee3, Yong Chan Lee4, Kyung-Min Lim7, James R Goldenring8, Ki Taek Nam9. 1. Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. 2. National Cancer Center, Kyeonggi-do, Korea. 3. Department of Life Science, Ewha Womans University, Seoul, Korea. 4. Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea. 5. Laboratory of Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea. 6. Department of Surgery, Gyeongsang National University Hospital, Jinju, Korea. 7. College of Pharmacy, Ewha Womans University, Seoul, Korea. Electronic address: kmlim@ewha.ac.kr. 8. Epithelial Biology Center and Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee. Electronic address: jim.goldenring@vumc.org. 9. Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. Electronic address: kitaek@yuhs.ac.
Abstract
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.
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.
Authors: Victoria G Weis; Josane F Sousa; Bonnie J LaFleur; Ki Taek Nam; Jared A Weis; Paul E Finke; Nadia A Ameen; James G Fox; James R Goldenring Journal: Gut Date: 2012-07-07 Impact factor: 23.059
Authors: Christine P Petersen; Anne R Meyer; Carlo De Salvo; Eunyoung Choi; Cameron Schlegel; Alec Petersen; Amy C Engevik; Nripesh Prasad; Shawn E Levy; R Stokes Peebles; Theresa T Pizarro; James R Goldenring Journal: Gut Date: 2017-02-14 Impact factor: 23.059
Authors: Kevin A Bockerstett; Luciana H Osaki; Christine P Petersen; Catherine W Cai; Chun Fung Wong; Thanh-Long M Nguyen; Eric L Ford; Daniel F Hoft; Jason C Mills; James R Goldenring; Richard J DiPaolo Journal: Cell Mol Gastroenterol Hepatol Date: 2018-01-02