STIM1 Deficiency In Intestinal Epithelium Attenuates Colonic Inflammation and Tumorigenesis by Reducing ER Stress of Goblet Cells.

Abstract

BACKGROUND & AIMS:

As an indispensable component of store-operated Ca2+ 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.

METHODS:

Inflammatory and matched normal intestinal tissues were collected from IBD patients to investigate the expression of STIM1. Intestinal epithelium-specific STIM1 conditional knockout mice (STIM1ΔIEC) 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.

RESULTS:

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 Ca2+ homeostasis, resulting in the maintenance of the integrated mucus layer. These effects prevented commensal bacteria from contacting and stimulating the intestinal epithelium of STIM1ΔIEC mice and thereby rendered STIM1ΔIEC mice less susceptible to colitis and colitis-associated colorectal cancer. In addition, microbial diversity in dextran sodium sulfate-treated STIM1ΔIEC mice slightly shifted to an advantageous bacteria, which further protected the intestinal epithelium.

CONCLUSIONS:

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.

• Authors: Xiaojing Liang, Jiansheng Xie, Hao Liu, Rongjie Zhao, Wei Zhang, Haidong Wang, Hongming Pan, Yubin Zhou, Weidong Han
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 14 Issue 1 Pg. 193-217 ( 2022) ISSN: 2352-345X [Electronic] United States
• PMID: 35367664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Neoplasm Proteins
• STIM1 protein, human
• Stim1 protein, mouse
• Stromal Interaction Molecule 1
• Dextran Sulfate

Topics

• Animals
• Carcinogenesis (metabolism)
• Cell Transformation, Neoplastic
• Colitis (chemically induced, complications, metabolism)
• Colitis-Associated Neoplasms
• Dextran Sulfate (toxicity)
• Goblet Cells (metabolism)
• Humans
• Inflammation (metabolism)
• Inflammatory Bowel Diseases
• Intestinal Mucosa (metabolism)
• Mice
• Neoplasm Proteins (deficiency, metabolism)
• Stromal Interaction Molecule 1 (genetics, metabolism)