Abstract
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.
Highlights
Colorectal cancer (CRC) is the third leading cause of cancer death worldwide [1]
Tipe2-deficiency resists aging, while the overexpression in CRC cells promotes cellular senescence To determine the roles of Tipe2 in senescence, we detected sera biochemical parameters from C57BL/6 (WT) and TIPE2-/- mice of
We found that the overexpression of Tipe2 upregulated the expression of TGF-β protein both in primary cultured 7th ASMC cells and CRC cells (Fig. 4C), accompanied by the upregulation of p-Smad3 (Fig. 2C)
Summary
Studies demonstrated that inflammatory bowel diseases (IBD) including ulcerative colitis (UC) and Crohn’s disease were chronic inflammatory disorders of the gastrointestinal tract, strongly suggesting association with an increased risk of CRC development [2,3,4]. Recent studies showed that CRC might be related to cellular senescence [5, 6]. The decline of immune function is thought to be tightly associated with age-related diseases, such as cancer [8,9,10]. The hallmarks of immune senescence include an inverse of CD4/CD8 ratio, a shift from naïve to memory T cell phenotype, poor T-cell proliferative responses to stimuli, an increase of pro-inflammatory cytokines (such as IL-1, IL-6, TNF-α), these age-related changes result in the failure of homeostasis [11,12,13,14]. Replicative senescence can be triggered by telomere shortening which is repaired and maintained by the activity of telomerase [15, 16]
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