Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, China.
Department of Blood Transfusion, Qilu Hospital of Shandong University, Ji'nan, People's Republic of China.
Cell Death Dis. 2021 Oct 26;12(11):1001. doi: 10.1038/s41419-021-04289-0.
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.
衰老是一个自然的、渐进的过程，其特征是与年龄相关的疾病（如癌症）的发生频率增加。但其机制尚不清楚。TNFAIP8L2（Tipe2）是一种重要的负调控因子，通过抑制 TLR 和 TCR 信号通路来维持内稳态。我们的工作揭示了 Tipe2 可能通过调节衰老具有双重功能。一方面，CRC 细胞中 Tipe2 的过表达可以诱导典型的衰老表型，尤其是暴露于氧化应激时。Tipe2 通过调节 c-Myc 和 c-Est-2 与 hTERT 启动子的结合来抑制端粒酶活性。有趣的是，与 WT 相比，用 D-Gal 处理的 Tipe2 KO 小鼠的 CD4：CD8 比值逆转不那么严重，Treg 的百分比更低。此外，Tipe2 KO 小鼠对 AOM/DSS 诱导的 CRC 的起始更耐受，伴随着 IEL 内 Treg 的水平降低。因此，针对 CD25 的特异性抗体可有效改善肿瘤发生。这些数据强烈表明，过表达的 Tipe2 抑制肿瘤细胞的增殖和存活，但内源性 Tipe2 促进肿瘤发生的启动，当暴露于危险环境如 AOM/DSS 相关炎症时。
