MicroRNA-105 is involved in TNF-α-related tumor microenvironment enhanced colorectal cancer progression
MicroRNA-105 is involved in TNF-α-related tumor microenvironment enhanced colorectal cancer progression
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MicroRNA-105 参与 TNF-α 相关的肿瘤微环境，增强结直肠癌的进展。
DOI：
10.1038/s41419-017-0048-x
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发表时间：
2017-12-13
影响因子：
9
通讯作者：
Zhao, Liang
中科院分区：
文献类型：
--
作者：
Shen, Zetao;Zhou, Rui;Zhao, Liang
TNF-α是肿瘤微环境中促进恶性肿瘤进展的中心促炎细胞因子。在这项研究中，我们发现miR-105在结直肠癌中的上调与侵袭性表型相关，并且miR-105的增强表达是TNF-α诱导的上皮-间质转化（EMT）所必需的。使用实时qPCR分析，TNF-α以时间依赖性方式显著刺激miR-105的表达。miR-105的抑制通过阻止NF-κ B信号的激活和EMT的启动而显著减弱TNF-α的侵袭作用。此外，miR-105被证明直接靶向RAP 2C的3 '-UTR，RAP 2C是小GTP结合蛋白的Rap 2亚家族。因此，RAP 2C的抑制可刺激miR-105的作用，从而显著促进CRC细胞的侵袭和转移。沙利度胺，一种TNF-α和NF-κ B抑制剂，显著削弱了miR-105过表达的CRC细胞在裸鼠中的转移和归巢能力。我们的研究初步阐明了miR-105在TNF-α诱导的EMT和进一步的CRC转移中的调节作用。我们还提供了一个更好的理解TNF α诱导的转移，并提出了一个有效的治疗策略，对CRC转移。
TNF-alpha is a central proinflammatory cytokine contributing to malignant tumor progression in tumor microenvironment. In this study, we found the upregulation of miR-105 in colorectal cancer was associated with aggressive phenotype, and the enhanced expression of miR-105 was required for TNF-alpha-induced epithelial-mesenchymal transition (EMT). The expression of miR-105 was remarkably stimulated by TNF-alpha in a time-dependent manner using real-time qPCR analysis. Inhibition of miR-105 remarkably weakened the aggressive effects of TNF-alpha through preventing the activation of NF-kappa B signaling and the initiation of EMT. Furthermore, miR-105 was demonstrated directly targeted on the 3'-UTRs of RAP2C, a Rap2 subfamily of small GTP-binding protein. Consistently, suppression of RAP2C stimulated the role of miR-105, which dramatically promoted the invasion and metastasis of CRC cells. Thalidomide, a TNF-alpha and NF-kappa B inhibitor, significantly weakened the metastasis and homing capacity of miR-105-overexpressed CRC cells in nude mice. Our investigation initiatively illustrated the modulatory role of miR-105 in TNF-alpha-induced EMT and further CRC metastasis. We also offer a better understanding of TNF alpha-induced metastasis and suggest an effective therapeutic strategy against CRC metastasis.