Novel transduction of nutrient stress to Notch pathway by RasGRP3 promotes malignant aggressiveness in human esophageal squamous cell carcinoma.

Abstract

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 γ-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.

• Authors: Ge Hu, Yuepeng Zhou, Yu Zhu, Ling Zhou, Rui Ling, Dan Wu, Lei Mi, Xuefeng Wang, Dongfang Dai, Chaoming Mao, Deyu Chen
• Journal: Oncology reports (Oncol Rep) Vol. 38 Issue 5 Pg. 2975-2984 (Nov 2017) ISSN: 1791-2431 [Electronic] Greece
• PMID: 29048643 (Publication Type: Journal Article)

Chemical References

• Guanine Nucleotide Exchange Factors
• Neoplasm Proteins
• RASGRP3 protein, human
• Receptors, Notch
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• ras Guanine Nucleotide Exchange Factors

Topics

• Adult
• Aged
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Epithelial-Mesenchymal Transition (genetics)
• Esophageal Neoplasms (genetics, metabolism, pathology)
• Esophageal Squamous Cell Carcinoma
• Female
• Food (adverse effects)
• Gene Expression Regulation, Neoplastic (genetics)
• Guanine Nucleotide Exchange Factors (genetics)
• Humans
• Male
• Middle Aged
• Neoplasm Invasiveness (genetics)
• Neoplasm Metastasis
• Neoplasm Proteins (genetics)
• Receptors, Notch (genetics)
• Signal Transduction (genetics)
• Vascular Endothelial Growth Factor A
• ras Guanine Nucleotide Exchange Factors