Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas.
Cell Mol Gastroenterol Hepatol. 2022;14(1):193-217. doi: 10.1016/j.jcmgh.2022.03.007. Epub 2022 Mar 31.
BACKGROUND & AIMS: As an indispensable component of store-operated Ca entry, stromal interaction molecule 1 (STIM1) is known to promote colorectal cancer and T-cell-mediated inflammatory diseases. However, whether the intestinal mucosal STIM1 is involved in inflammatory bowel diseases (IBDs) is unclear. This study aimed to investigate the role of intestinal epithelial STIM1 in IBD.
Inflammatory and matched normal intestinal tissues were collected from IBD patients to investigate the expression of STIM1. Intestinal epithelium-specific STIM1 conditional knockout mice (STIM1) were generated and induced to develop colitis and colitis-associated colorectal cancer. The mucosal barrier, including the epithelial barrier and mucus barrier, was analyzed. The mechanisms by which STIM1 regulate goblet cell endoplasmic reticulum stress and apoptosis were assessed.
STIM1 could regulate intestinal epithelial homeostasis. STIM1 was augmented in the inflammatory intestinal tissues of IBD patients. In dextran sodium sulfate-induced colitis, STIM1 deficiency in intestinal epithelium reduced the loss of goblet cells through alleviating endoplasmic reticulum stress induced by disturbed Ca homeostasis, resulting in the maintenance of the integrated mucus layer. These effects prevented commensal bacteria from contacting and stimulating the intestinal epithelium of STIM1 mice and thereby rendered STIM1 mice less susceptible to colitis and colitis-associated colorectal cancer. In addition, microbial diversity in dextran sodium sulfate-treated STIM1 mice slightly shifted to an advantageous bacteria, which further protected the intestinal epithelium.
Our results establish STIM1 as a crucial regulator for the maintenance of the intestinal barrier during colitis and provide a potential target for IBD treatment.
作为钙库操作型钙内流的不可或缺组成部分，基质相互作用分子 1（STIM1）被认为可促进结直肠癌和 T 细胞介导的炎症性疾病。然而，肠道黏膜 STIM1 是否参与炎症性肠病（IBD）尚不清楚。本研究旨在探究肠上皮 STIM1 在 IBD 中的作用。
收集 IBD 患者的炎症和匹配的正常肠道组织，以研究 STIM1 的表达情况。生成并诱导肠上皮细胞特异性 STIM1 条件性敲除小鼠（STIM1）发生结肠炎和结肠炎相关结直肠癌。分析黏膜屏障，包括上皮屏障和黏液屏障。评估 STIM1 调节杯状细胞内质网应激和凋亡的机制。
STIM1 可调节肠上皮细胞稳态。在 IBD 患者的炎症性肠道组织中，STIM1 增加。在葡聚糖硫酸钠诱导的结肠炎中，肠上皮细胞中的 STIM1 缺失通过减轻钙稳态紊乱引起的内质网应激，减少杯状细胞的丢失，从而维持完整的黏液层。这些作用阻止了共生细菌与 STIM1 小鼠的肠上皮接触和刺激，从而使 STIM1 小鼠不易发生结肠炎和结肠炎相关结直肠癌。此外，葡聚糖硫酸钠处理的 STIM1 小鼠中的微生物多样性略有向有益细菌转移，这进一步保护了肠上皮。
我们的研究结果确立了 STIM1 作为结肠炎期间维持肠道屏障的关键调节剂，并为 IBD 治疗提供了一个潜在的靶点。
