Novel transduction of nutrient stress to Notch pathway by RasGRP3 promotes malignant aggressiveness in human esophageal squamous cell carcinoma
Novel transduction of nutrient stress to Notch pathway by RasGRP3 promotes malignant aggressiveness in human esophageal squamous cell carcinoma
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RasGRP3将营养应激转导至Notch通路可促进人食管鳞状细胞癌的恶性侵袭
DOI：
10.3892/or.2017.5996
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发表时间：
2017-11-01
期刊：
影响因子：
4.2
通讯作者：
Chen, Deyu
中科院分区：
文献类型：
--
作者：
Hu, Ge;Zhou, Yuepeng;Chen, Deyu
在肿瘤扩大的过程中，组织结构的溶解和内皮细胞的重塑，以恢复气体交换和营养支持，进一步促进肿瘤细胞的侵袭和转移。Ras的激活在食管鳞状细胞癌（ESCC）的发生发展中起着关键作用，但其潜在机制仍知之甚少。因此，我们研究了Ras鸟苷酸释放蛋白3（RasGRP 3），Ras激活剂，是否可以通过诱导血管再生和营养应激（NS）下的上皮-间充质转化促进转移。在本研究中，我们探讨了RasGRP 3的积累调节血管内皮生长因子-A的产生，共刺激Notch通路与高表达的Notch胞内结构域（NICD）和Hes 1。此外，NS下的ESCC细胞增加了波形蛋白、Snail、Slug和MMP 9蛋白的表达;而DAPT抑制Notch活化（a.分泌酶抑制剂）或RasGRP 3靶向RNA干扰可以阻止该效应。总之，这些研究结果提供了一个新的见解上调RasGRP 3参与Notch途径激活ESCC的发展，特别是在营养剥夺。
In the process of enlarging of tumors, the dissolving tissue structures and remodeling endothelial cells for restoring gas exchange and nutritional support, further facilitate tumor cell invasion and metastasis. Activation of Ras plays a critical role in the development of esophageal squamous cell carcinoma (ESCC), but the underlying mechanisms remain poorly understood. We therefore investigated whether Ras guanyl-releasing protein 3 (RasGRP3), a Ras activator, could promote metastasis by inducing vascular regeneration and further epithelial-mesenchymal transition under nutrient stress (NS). In the present study, we explored that the accumulation of RasGRP3 regulated vascular endothelial growth factor-A production, co-stimulated Notch pathway with high expression of Notch intracellular domain (NICD) and Hes1. Moreover, ESCC cells under NS increased the expression of vimentin, Snail, Slug and MMP9 proteins; while inhibition of Notch activation by DAPT (a.-secretase inhibitor) or RasGRP3-targeted RNA interference prevented from the effect. In conclusion, these findings provide a new insight into the upregulation of RasGRP3 involved in Notch pathway activation in the development of ESCC, especially under nutrient deprivation.