Tumor necrosis factor-α-induced protein 8-like 2 Fosters Tumor-Associated Microbiota to Promote the Development of Colorectal Cancer

Although increasing evidence links the gut microbiota with the development of colorectal cancer, the molecular mechanisms for microbiota regulation of tumorigenesis are not fully understood. Here, we found that a member of the TNF-α-induced protein 8 (TNFAIP8) family called TIPE2 (TNFAIP8-like 2) was significantly upregulated in murine intestinal tumors and in human colorectal cancer (CRC), and colorectal cancer with high expression of Tipe2 mRNA associated with reduced survival time of patients. Consistent with these findings, TIPE2 deficiency significantly inhibited the development of CRC in mice treated with azoxymethane/dextran sodium sulfate and in Apcmin/+ mice. TIPE2 deficiency attenuated the severity of colitis by successfully resolving and restricting colonic inflammation and protected colonic myeloid cells from death during colitis. Transplantation of TIPE2-deficient bone marrow into WT mice successfully dampened the latter's tumorigenic phenotype, indicating a hematopoietic-specific role for TIPE2. Mechanistically, restricting the expansion of Enterobacteriaceae/E. coli decreased intestinal inflammation and reduced the incidence of colonic tumors. Collectively, these data suggest that hematopoietic TIPE2 regulates intestinal anti-tumor immunity by regulation of gut microbiota. TIPE2 may represent a new therapeutic target for treating CRC.