NDRG2 regulates adherens junction integrity to restrict colitis and tumourigenesis
Mengying Wei,
Yongzheng Ma,
Liangliang Shen,
Yuqiao Xu,
Lijun Liu,
Xin Bu,
Zhihao Guo,
Hongyan Qin,
Zengshan Li,
Zhe Wang,
Kaichun Wu,
Libo Yao,
Jipeng Li,
Jian Zhang
Affiliations
Mengying Wei
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an 710032, China
Yongzheng Ma
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an 710032, China
Liangliang Shen
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an 710032, China
Yuqiao Xu
The State Key Laboratory of Cancer Biology, Department of Pathology, the Fourth Military Medical University, Xi'an 710032, China
Lijun Liu
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an 710032, China
Xin Bu
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an 710032, China
Zhihao Guo
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an 710032, China
Hongyan Qin
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China
Zengshan Li
The State Key Laboratory of Cancer Biology, Department of Pathology, the Fourth Military Medical University, Xi'an 710032, China
Zhe Wang
The State Key Laboratory of Cancer Biology, Department of Pathology, the Fourth Military Medical University, Xi'an 710032, China
Kaichun Wu
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Disease, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
Libo Yao
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an 710032, China
Jipeng Li
State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi'an, China; Department of Experimental Surgery, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, China; Corresponding author at: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, 710032 Xi'an, China.
Jian Zhang
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an 710032, China; Corresponding author at: State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi'an, China.
Background: Paracellular barriers play an important role in the pathogenesis of Inflammatory bowel disease (IBD) and maintain gut homeostasis. N-myc downstream-regulated gene 2 (NDRG2) has been reported to be a tumour suppressor gene and to inhibit colorectal cancer metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated colorectal cancer is unclear. Methods: Intestine-specific Ndrg2 deficiency mice (Ndrg2ΔIEC) were subjected to DSS- or TNBS-induced colitis, and AOM-DSS-induced colitis-associated tumour. HT29 cells, Caco2 cells, primary intestinal epithelial cells (IECs) from Ndrg2ΔIEC mice, mouse embryo fibroblasts (MEFs) from systemic Ndrg2 knockout mice, HEK293 cells and human UC and DC specimens were used to investigate NDRG2 function in colitis and colitis-associated tumour. Findings: Ndrg2 loss led to adherens junction (AJ) structure destruction via E-cadherin expression attenuation, resulting in diminished epithelial barrier function and increased intestinal epithelial permeability. Mechanistically, NDRG2 enhanced the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail degradation by ubiquitination and maintained E-cadherin expression. In human ulcerative colitis patients, reduced NDRG2 expression is positively correlated with severe inflammation. Interpretation: These findings demonstrate that NDRG2 is an essential colonic epithelial barrier regulator and plays an important role in gut homeostasis maintenance and colitis-associated tumour development. Funding: National Natural Science Foundation of China (No. 81770523, 31571437, 81672751), Creative Research Groups of China (No. 81421003), State Key Laboratory of Cancer Biology Project (CBSKL2019ZZ11, CBSKL201406, CBSKL2017Z08 and CBSKL2017Z11), Fund for Distinguished Young Scholars of ShaanXi province (2019JC-22).
