TNFAIP8 protein functions as a tumor suppressor in inflammation-associated colorectal tumorigenesis

• Published in: Cell death & disease 2022-04, Vol.13 (4), p.311-10, Article 311
• Main Authors: Lou, Yunwei, Tian, Xueqin, Sun, Chen, Song, Miaomiao, Han, Meijuan, Zhao, Yuxin, Song, Yaru, Song, Xiangfeng, Zhang, Wen, Chen, Youhai H., Wang, Hui
• Format: Article
• Language: English
• Subjects: 38/23; 631/250/256/2515; 64/60; 692/699/67/327; 96/21; Animals; Antibodies; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Carcinogenesis; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell Biology; Cell Culture; Cell proliferation; Cell Transformation, Neoplastic - metabolism; Colitis; Colitis - chemically induced; Colitis - complications; Colitis - genetics; Colitis-Associated Neoplasms; Colon cancer; Colorectal cancer; DNA damage; Dysbacteriosis; Dysplasia; Epithelial cells; Humans; Immunology; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammatory bowel disease; Intestine; Life Sciences; Mice; Mice, Inbred C57BL; Microbiota; mRNA; NF-κB protein; Stat3 protein; Tumor necrosis factor-α; Tumor suppressor genes; Tumorigenesis
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04769-x

Tumor necrosis factor-α-induced protein 8 (TNFAIP8 or TIPE) is a member of the TNFAIP8 family. While TIPE was broadly considered to be pro-cancerous, its precise roles in carcinogenesis especially those of the intestinal tract are not clear. Here, we show that genetic deletion of TIPE in mice exacerbated chemical-induced colitis and colitis-associated colon cancer. Loss of TIPE exacerbated inflammatory responses and inflammation-associated dysbiosis, leading to the activation of NF-κB and STAT3, and it also accelerated dysplasia, DNA damage and proliferation of intestinal epithelial cells. We further show that colon microbiota were essential for increased tumor growth and progression in Tipe −/− mice. The tumor suppressive function of TIPE originated primarily from the non-hematopoietic compartment. Importantly, TIPE was downregulated in human colorectal cancers, and patients with low levels of Tipe mRNA were associated with reduced survival. These results indicate that TIPE serves as an important modulator of colitis and colitis-associated colon cancer.