Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, 110001, China.
Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, 110001, China.
Cell Biol Int. 2018 May;42(5):506-514. doi: 10.1002/cbin.10924. Epub 2018 Jan 25.
Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) triggers apoptosis by inducing the death-inducing signaling complex (DISC) formation. Recently, TNFα-induced protein 3 (TNFAIP3, A20) was reported to prevent TRAIL-induced caspase 8 cleavage in the DISC by mediating ubiquitination of RIP1 in glioblastoma. However, whether A20 regulates caspase 8 cleavage in the DISC when TRAIL induces apoptosis in gastric cancer cells is unknown. In the present study, A20 interacted with RIP1 and DR4 in MGC803 and SGC7901 gastric cancer cells. Treatment with TRAIL promoted the A20-mediated polyubiquitination of RIP1, caspase 8 translocation into the DISC, and the interaction between caspase 8 and ubiquitinated RIP1. Inhibition of A20 expression prevented the polyubiquitination of RIP1 and promoted caspase 8 cleavage. Moreover, our data clarified that A20 is a target of miR-200a. Overexpression of miR-200a inhibited A20 expression and polyubiquitination of RIP1 and then promoted cleavage of caspase 8 and TRAIL-triggered apoptosis. Taken together, our results indicate that miR-200a enhanced TRAIL-triggered apoptosis in gastric cancer cells by targeting A20.
肿瘤坏死因子-α相关凋亡诱导配体（TRAIL）通过诱导死亡诱导信号复合物（DISC）的形成触发细胞凋亡。最近，据报道 TNFα 诱导蛋白 3（TNFAIP3，A20）通过介导 RIP1 的泛素化来防止 DISC 中 TRAIL 诱导的半胱天冬酶 8 切割，从而在神经胶质瘤中。然而，当 TRAIL 在胃癌细胞中诱导细胞凋亡时，A20 是否调节 DISC 中的半胱天冬酶 8 切割尚不清楚。在本研究中，A20 在 MGC803 和 SGC7901 胃癌细胞中与 RIP1 和 DR4 相互作用。用 TRAIL 处理可促进 A20 介导的 RIP1 多泛素化、半胱天冬酶 8 易位到 DISC 以及半胱天冬酶 8 和泛素化 RIP1 之间的相互作用。抑制 A20 表达可防止 RIP1 的多泛素化并促进半胱天冬酶 8 的切割。此外，我们的数据阐明了 A20 是 miR-200a 的靶标。miR-200a 的过表达抑制 A20 的表达和 RIP1 的多泛素化，然后促进半胱天冬酶 8 的切割和 TRAIL 触发的细胞凋亡。总之，我们的结果表明，miR-200a 通过靶向 A20 增强了胃癌细胞中 TRAIL 触发的细胞凋亡。
