CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages.
CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-α-induced apoptosis by tumor-associated macrophages.
复制标题
DOI：
10.1186/1471-2407-14-949
复制
发表时间：
2014-12-15
期刊：
影响因子：
3.8
通讯作者：
Koizumi K
中科院分区：
文献类型：
--
作者：
Kee JY;Ito A;Hojo S;Hashimoto I;Igarashi Y;Tsuneyama K;Tsukada K;Irimura T;Shibahara N;Takasaki I;Inujima A;Nakayama T;Yoshie O;Sakurai H;Saiki I;Koizumi K
通过上调免疫监视来抑制肿瘤转移是趋化因子基因治疗的主要目的。在这项研究中，我们重点研究了一种膜结合的趋化因子CXCL16，它与结直肠癌(CRC)患者的良好预后相关。我们建立了一个表达CXCL16的转移性CRC细胞系，并鉴定了肿瘤坏死因子和凋亡相关因子的变化。为了探讨CXCL16对结直肠癌肝转移的影响，我们将SL4-Cont和SL4-CXCL16细胞分别注入C57BL/6小鼠的门静脉内，并对其转移情况进行了评价。此外，我们用流式细胞术分析了转移肝组织中CXCL16的表达是否调节了M1巨噬细胞的渗透。CXCL16的表达通过激活PARP和Caspase3介导的凋亡通路以及通过失活NF-αB介导的生存通路来增强肿瘤坏死因子-κ诱导的细胞凋亡。CXCL16的表达改变了几个基因，但我们关注的是IRF8，它是细胞凋亡和转移表型的调节因子。我们证实了CXCL16在SL4-CXCL16细胞中的表达以及CXCL16与IRF8的相关性。沉默IRF8可显著减少肿瘤坏死因子-α诱导的细胞凋亡。肿瘤坏死因子-α通过诱导M1巨噬细胞释放肿瘤坏死因子-α诱导细胞凋亡，从而抑制肝转移。提示CXCL16可促进M1巨噬细胞聚集和促进细胞凋亡，可能是一种有效的抗结直肠癌肝转移的双重途径。总之，这项研究揭示了CXCL16调节免疫监视和细胞信号。因此，我们首次提供了CXCL16作为细胞内信号分子的证据。本文的在线版本(DOI：10.1186/1471-2407-14-949)包含补充材料，可供授权用户使用。
Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients. We generated a CXCL16-expressing metastatic CRC cell line and identified changes in TNF and apoptosis-related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages. CXCL16 expression enhanced TNF-α-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-κB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-α-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-α-induced apoptosis through the induction of M1 macrophages, which released TNF-α. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis. Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule. The online version of this article (doi:10.1186/1471-2407-14-949) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
4.4
作者：
Liu, KB;Abrams, SI
通讯作者：
Abrams, SI
影响因子：
20.3
作者：
Kim, CH;Johnston, B;Butcher, EC
通讯作者：
Butcher, EC
DOI：
10.1073/pnas.87.10.3743
发表时间：
1990-05-01
影响因子：
11.1
作者：
DRIGGERS, PH;ENNIST, DL;OZATO, K
通讯作者：
OZATO, K
影响因子：
4.4
作者：
Abel, S;Hundhausen, C;Ludwig, A
通讯作者：
Ludwig, A
影响因子：
6.4
作者：
KELKER, HC;OPPENHEIM, JD;VILCEK, J
通讯作者：
VILCEK, J