Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, China.
Mol Cells. 2018 Jul 31;41(7):653-664. doi: 10.14348/molcells.2018.0040. Epub 2018 Jun 25.
The RNA-binding protein tristetraprolin (TTP) binds to adenosine-uridine AU-rich elements in the 3'-untranslated region of messenger RNAs and facilitates rapid degradation of the target mRNAs. Therefore, it regulates the expression of multiple cancer and immunity-associated transcripts. Furthermore, a lack of TTP in cancer cells influences cancer progression and predicts poor survival. Although the functions of TTP on cancer cells have previously been researched, the mechanism of TTP on the interaction between cancer cells with their microenvironment remains undiscovered. In this study, we admed to determine the role of cancer cell TTP during the interaction between tumor and immune cells, specifically regulatory T cells (Tregs). We evaluate the capability of TTP to modulate the antitumor immunity of GC and explored the underlying mechanism. The overexpression of TTP in GC cells dramatically increased peripheral blood mononuclear lymphocyte (PBML) -mediated cytotoxicity against GC cells. Increased cytotoxicity against TTP-overexpressed GC cells by PBMLs was determined by Treg development and infiltration. Surprisingly, we found the stabilization of programmed death-ligand 1 (PD-L1) mRNA was declining while TTP was elevated. The PD-L1 protein level was reduced in TTP-abundant GC cells. PD-L1 gas been found to play a pivotal role in Treg development and functional maintenance in immune system. Taken together, our results suggest the overexpression of TTP in GC cells not only affects cell survival and apoptosis but also increases PBMLs -mediated cytotoxicity against GC cells to decelerate tumor progression. Moreover, we identified PD-L1 as a critical TTP-regulated factor that contributes to inhibiting antitumor immunity.
RNA 结合蛋白 tristetraprolin（TTP）与信使 RNA 的 3'非翻译区中的腺苷-尿嘧啶 AU 丰富元件结合，并促进靶 mRNA 的快速降解。因此，它调节多种癌症和免疫相关转录物的表达。此外，癌细胞中 TTP 的缺乏会影响癌症进展并预测预后不良。尽管先前已经研究了 TTP 对癌细胞的功能，但 TTP 对癌细胞与其微环境之间相互作用的机制仍未被发现。在这项研究中，我们旨在确定癌细胞 TTP 在肿瘤细胞与免疫细胞（特别是调节性 T 细胞（Tregs））相互作用过程中的作用。我们评估了 TTP 调节 GC 抗肿瘤免疫的能力，并探讨了潜在的机制。GC 细胞中 TTP 的过表达显着增加了外周血单核细胞（PBML）对 GC 细胞的细胞毒性。通过 Treg 发育和浸润来确定 PBML 对 TTP 过表达 GC 细胞的杀伤活性增加。令人惊讶的是，我们发现程序性死亡配体 1（PD-L1）mRNA 的稳定性在 TTP 升高时下降。TTP 丰富的 GC 细胞中的 PD-L1 蛋白水平降低。PD-L1 在免疫系统中被发现对 Treg 的发育和功能维持起着关键作用。总之，我们的结果表明，GC 细胞中 TTP 的过表达不仅影响细胞存活和凋亡，而且增加了 PBML 对 GC 细胞的细胞毒性，从而减缓肿瘤进展。此外，我们确定 PD-L1 是 TTP 调节的关键因子，有助于抑制抗肿瘤免疫。
