E2F-1 promotes DAPK2-induced anti-tumor immunity of gastric cancer cells by targeting miR-34a
E2F-1 promotes DAPK2-induced anti-tumor immunity of gastric cancer cells by targeting miR-34a
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E2F-1通过靶向miR-34a促进DAPK2诱导的胃癌细胞的抗肿瘤免疫
DOI：
10.1007/s13277-016-5446-7
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Chen Jian Si
中科院分区：
文献类型：
--
作者：
Yan Lin Hai;Chen Zhi Ning;Li Li;Chen Jia;Mo Xian Wei;Qin Yu Zhou;Wei Wen E;Qin Hai Quan;Lin Yuan;Chen Jian Si
转录因子E2F-1基因的激活是树突状细胞(DC)成熟过程中的一个负性事件。E2F1的下调导致DC不成熟，从而停止抗原的产生，进而导致免疫反应的抑制。不含E2F-1的E2F-1刺激了核因子-kB信号通路，导致单核细胞和其他几个转录因子基因的激活。在这项研究中，我们报道了DC中E2F-1的下调通过一种新的机制促进了胃癌细胞的抗肿瘤免疫反应。从外周血单核细胞中分离出DC。E2F-1小干扰RNA(E2F-1-shRNA)可下调DC中E2F-1mRNA和蛋白的表达。进一步，我们鉴定了E2F-1-shRNA靶向CD80、CD83、CD86和MHC II分子，促进其表达，并诱导T淋巴细胞增殖活性、上调干扰素-Ī的产生和GC细胞杀伤效应，这与E2F-1-shRNA DC激活的细胞毒性T细胞显著相关。MiR-34a的高表达与DC增强抗胃癌细胞的抗肿瘤免疫密切相关，miR-34a主要针对DAPK2和Sp1，两者都参与了E2F-1的失活。此外，在小鼠E2F-1-DC下调中，GC移植瘤表现出Sp1、DAPK2、Caspase3和Caspase7的下调，并进展为抗肿瘤免疫。总之，我们的数据揭示了E2F-1通过依赖miR-34a下调E2F-1表达来控制DC抗肿瘤免疫的机制，并提示其对GC免疫治疗的贡献。
Activation of the transcription factor E2F-1 gene is a negative event in dendritic cell (DC) maturation process. Down-regulation of E2F1 causes immaturity of DC thereby stopping antigen production which in turn leads to inhibition of immune responses. E2F-1-free stimulates the NF-kB signaling pathway, leading to activation of monocytes and several other transcription factor genes. In the study, we report that down-regulation of E2F-1 in DCs promote anti-tumor immune response in gastric cancer (GC) cells through a novel mechanism. DCs were isolated from peripheral blood mononuclear cells. E2F-1 small interfering RNA (E2F-1-shRNA) induced down-regulation of E2F-1 mRNA and protein expression in DCs. Furthermore, we identified the E2F-1-shRNA targeted the CD80, CD83, CD86, and MHC II molecules, promoted their expression, and induced T lymphocytes proliferation activity and up-regulation of IFN-Ī³ production and GC cell killing effect, which significantly correlated with the cytotoxic T lymphocytes activated by E2F-1-shRNA DCs. The higher expression of miR-34a was found which was significantly correlated with the DC enhancing anti-tumor immunity against gastric cancer cell, and miR-34a potently targeted DAPK2 and Sp1, both of which were involved in the deactivation of E2F-1. Moreover, in E2F-1-DC-down-regulation in mice, GC transplantation tumors displayed down-regulation of Sp1, DAPK2, Caspase3, and Caspase7 and progressed to anti-tumor immunity. Collectively, our data uncover an E2F-1-mediated mechanism for the control of DC anti-tumor immunity via miR-34a-dependent down-regulation of E2F-1 expression and suggest its contribution to GC immunotherapy.
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影响因子：
--
作者：
Xu X;Chen W;Miao R;Zhou Y;Wang Z;Zhang L;Wan Y;Dong Y;Qu K;Liu C
通讯作者：
Liu C
影响因子：
8
作者：
Britschgi, A.;Trinh, E.;Tschan, M. P.
通讯作者：
Tschan, M. P.
影响因子：
158.5
作者：
Kantoff, Philip W.;Higano, Celestia S.;Young, J.
通讯作者：
Young, J.
DOI：
10.1056/nejmc1009982
发表时间：
2010-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
T. Tanimoto;A. Hori;M. Kami
通讯作者：
T. Tanimoto;A. Hori;M. Kami
影响因子：
5.3
作者：
Zhu, JW;Field, SJ;DeGregori, J
通讯作者：
DeGregori, J