전암병변인 화생에서 HE4의 역할에 관한 연구

Human epididymis protein (HE4), also known as WFDC2 is a member of a larger family of WAP domain containing secreted putative extracellular protease inhibitor proteins. HE4 is highly expressed in epithelial ovarian cancer and up-regulated in spasmolytic polypeptide expressing gastric metaplasia (SPEM) whereas it is present at low or non-expression levels in normal human and mouse tissues. SPEM characterized as loss of parietal cell (oxyntic atrophy), is the primary event in the pathogenesis of gastric cancer. Loss of parietal cell is highly associated with Helicobacter pylori infection which induced chronic gastritis and increased risk of gastric adenocarcinoma. Although previous studies suggested that a direct linkage between HE4 expression and SPEM, its molecular mechanisms in the process of metaplasia have not been fully understood and most studies are exclusively focused on clinical application as a preneoplastic biomarker. In this study, I investigated the effect of HE4 expression in gastric microenvironment on metaplasia using HE4 knockout mice (HE4 KO). To assess the effect of HE4 on stomach homeostasis and metaplasia, I used three models for pharmacological induction of acute oxyntic atrophy with DMP-777, L-635 and High dose tamoxifen. High dose tamoxifen, a selective estrogen receptor modulator, intraperitoneal injection caused apoptosis of >90% of all parietal cells and SPEM within 3 days. Like a DMP-777, gastric histology returns to nearly normal by 3 weeks. I clearly observed that pharmacological induced oxyntic atrophy and SPEM was inhibited in HE4 KO mice compared to WT mice. Also, I performed reconstitution of recombinant HE4 (rHE4) using osmotic pump to identify whether systemic HE4 process of metaplasia. Although HE4 is rarely expressed in normal gastric gland, blood circulating-rHE4 effectively regenerated SPEM in HE4 KO mice. proliferating SPEM cells were arising from base of gastric gland and parietal cell was ablated from fundic region in HE4 KO mice that were pre-injected rHE4 before DMP-777 treatment. Those phenotypical alteration was not distinguished with WT mice that also pre-injected rHE4. pharmacological induced oxyntic atrophy and SPEM While loss of HE4 did not induced severe gastric lesion or SPEM in normal condition, immune cell population residing in gastric gland was considerably different between two groups. I demonstrated that M1 macrophage was significantly increased in HE4 KO mice but M2 macrophage population was not changed between two groups. Also, depletion of M1 macrophage in HE4 KO mice promoted pharmacological induced oxyntic atrophy and SPEM. Taken together, the secretory HE4 play a crucial role in oxyntic atrophy induced metaplasia development and loss of HE4 might inhibit SPEM via tumor suppression effect of M1 macrophage.open석