GOLM1 restricts colitis and colon tumorigenesis by ensuring Notch signaling equilibrium in intestinal homeostasis

Yang Pu,Di Jin,Jianxin Cui,Yong Zhao,Ya Song,Fei Pan,Jie Li,Yanan Xu,Xinyu Zhang,Yinzhe Xu,Mengdi Zhang,Caifeng Long,Yanan Wang,Hongbing Zhang,Yan Li,Hongying Wang,Na Zhao

doi:10.1038/s41392-021-00535-1

Abstract

Intestinal epithelium serves as the first barrier against the infections and injuries that mediate colonic inflammation. Colorectal cancer is often accompanied with chronic inflammation. Differed from its well-known oncogenic role in many malignancies, we present here that Golgi membrane protein 1 (GOLM1, also referred to as GP73) suppresses colorectal tumorigenesis via maintenance of intestinal epithelial barrier. GOLM1 deficiency in mice conferred susceptibility to mucosal inflammation and colitis-induced epithelial damage, which consequently promoted colon cancer. Mechanistically, depletion of GOLM1 in intestinal epithelial cells (IECs) led to aberrant Notch activation that interfered with IEC differentiation, maturation, and lineage commitment in mice. Pharmacological inhibition of Notch pathway alleviated epithelial lesions and restrained pro-tumorigenic inflammation in GOLM1-deficient mice. Therefore, GOLM1 maintains IEC homeostasis and protects against colitis and colon tumorigenesis by modulating the equilibrium of Notch signaling pathway.

Highlights

Colorectal cancer (CRC) is the third leading cause of cancer-related death, with ~1.8 million new cases diagnosed worldwide in 2018.1 Patients with inflammatory bowel diseases (IBD), such as Crohn’s disease or ulcerative colitis (UC), are more susceptible to CRC
GOLM1-deficient mice are predisposed to AOM/DSS-induced colon tumorigenesis By comparing GOLM1 mRNA expression in normal and cancerous colon tissues from human patient biopsies based on TCGA database, we found GOLM1 expression was significantly lower in
Epithelial tight junction (TJ) stability is considered as another crucial factor of modulating intestinal permeability and epithelial integrity, we found no difference in the expression of key genes involved in TJ regulation and no significant morphological changes of TJ between Golm1−ΔIEC and Golm1−flox/flox mice (Supplementary Fig. 4i, j)

Summary

Introduction

Colorectal cancer (CRC) is the third leading cause of cancer-related death, with ~1.8 million new cases diagnosed worldwide in 2018.1 Patients with inflammatory bowel diseases (IBD), such as Crohn’s disease or ulcerative colitis (UC), are more susceptible to CRC. This type of CRC is referred as colitis-associated colorectal cancer (CAC),[2] which causes 10–15% of the annual deaths in IBD patients.[3,4,5] Among the various causes of colitis and CAC, the disrupted intestinal barrier is an important predisposing factor for disease progression.[6] The functional coordination of the intestinal barrier depends on the integrity of the epithelial layer and host immune responses. The repetitive injuries result in sustained inflammation, excessive tissue regeneration, and hyperplasia which eventually promote colonic carcinogenesis.[8,9] mice deficient in epithelial barrier have shown increased vulnerability to colitis and CAC.[10,11,12,13] Despite the known importance of the intestinal epithelial barrier in colorectal tumorigenesis, its underlying molecular mechanisms in tumor formation and development remain unclear

Methods

Results

Conclusion