The overexpression of Tipe2 in CRC cells suppresses survival while endogenous Tipe2 accelerates AOM/DSS induced-tumor initiation

Aging is a natural and progressive process characterized by an increased frequency of age-related diseases such as cancer. But its mechanism is unclear. TNFAIP8L2 (Tipe2) is an important negative regulator for homeostasis through inhibiting TLR and TCR signaling. Our work reveals that Tipe2 might have dual function by regulating senescence. One side, the overexpression of Tipe2 in CRC cells could induce typical senescent phenotype, especially exposure to oxidative stress. Tipe2 inhibits telomerase activity by regulating c-Myc and c-Est-2 binding to the hTERT promotor. Interestingly, Tipe2 KO mice treated with D-Gal showed a less serious inverse of CD4:CD8 ratio, a lower percentage of Treg compared to WT. Besides, Tipe2 KO mice were more tolerant to the initiation of AOM/DSS-induced CRC, accompanied by a lower level of Treg within IEL. Therefore, specific antibodies against CD25 effectively ameliorate tumorigenesis. These data suggest strongly that the overexpressed Tipe2 suppresses tumor cells proliferation and survival, but endogenous Tipe2 promotes the initiation of tumorigenesis when exposure to dangerous environment such as AOM/DSS-related inflammation.