Changsha Cancer Institute, Changsha Central Hospital, Changsha, Hunan 410004, China; Graduate School, University of South China, Hengyang, Hunan 421001, China.
Changsha Cancer Institute, Changsha Central Hospital, Changsha, Hunan 410004, China.
Int Immunopharmacol. 2018 Jan;54:296-302. doi: 10.1016/j.intimp.2017.11.027. Epub 2017 Nov 24.
Ubiquitin editing enzyme A20 functions as a tumor suppressor in various cancer. However, the mechanism for A20 regulation of cancer progress is not fully understood. In this study, we found that in human colorectal cancer HCT116 cells, TNFα induced a tolerant production of CXC chemokines, including CXCL1, 2, and 8 in a dose and time dependent manner. TNFα pre-treatment of HCT116 cells down-regulated the chemokine production induced by TNFα re-treatment. TNFα induced the phosphorylation of MAPKs ERK, JNK, P38 and NF-κB P65, but only ERK inhibition decreased TNFα-induced chemokine production. Both RT-PCR and FACS results showed that TNFα treatment did not regulate the expression of TNF receptors. However, TNFα up-regulated the expression of A20 at both mRNA and protein levels significantly. TNFα pre-treatment inhibited the signal transduction of MAPKs induced by TNFα re-stimulation, and A20 over-expression decreased the signal transduction of ERK and P38. Meanwhile, A20 inhibition by RNA interference reversed chemokine down-regulation induced by TNFα re-stimulation after TNFα pre-treatment. Taken together, these results suggested that in human colorectal cancer cells, A20 may function to inhibit cancer progression via down-regulation of TNFα-induced chemokine production by suppression of ERK signaling.
泛素编辑酶 A20 在多种癌症中作为肿瘤抑制因子发挥作用。然而，A20 调节癌症进展的机制尚未完全阐明。在本研究中，我们发现人结直肠癌细胞 HCT116 中，TNFα 以剂量和时间依赖的方式诱导 CXCL1、2 和 8 等 CXC 趋化因子的耐受产生。TNFα 预处理 HCT116 细胞可下调 TNFα 再处理诱导的趋化因子产生。TNFα 诱导 MAPKs ERK、JNK、P38 和 NF-κB P65 的磷酸化，但只有 ERK 抑制可降低 TNFα 诱导的趋化因子产生。RT-PCR 和 FACS 结果均表明 TNFα 处理不调节 TNF 受体的表达。然而，TNFα 可显著上调 A20 的 mRNA 和蛋白水平表达。TNFα 预处理可抑制 TNFα 再刺激诱导的 MAPKs 信号转导，A20 过表达可降低 ERK 和 P38 的信号转导。同时，TNFα 预处理后 RNA 干扰抑制 A20 可逆转 TNFα 再刺激诱导的趋化因子下调。综上所述，这些结果表明，在人结直肠癌细胞中，A20 可能通过抑制 ERK 信号转导下调 TNFα 诱导的趋化因子产生来抑制癌症进展。
