Targeting the VEGF-C/VEGFR3 axis suppresses Slug-mediated cancer metastasis and stemness via inhibition of KRAS/YAP1 signaling.

Abstract

Vascular endothelial growth factor-C (VEGF-C) has been implicated in epithelial-mesenchymal transition (EMT) processes and various human cancers, including skin cancer. Skin cancer is an aggressive human malignancy with increasing incidence worldwide; however, the underlying mechanisms involved in VEGF-C-induced skin cancer stemness and metastasis remain unclear. Here, we report that VEGF-C enhances skin cancer migration, invasion and stemness through Slug up-regulation. Oncomine database analysis indicated that the KRAS/MAPK (mitogen-activated protein kinases) pathway and YAP1 (yes-associated protein 1) expression are positively correlated with metastatic skin cancer. We show that VEGF-C triggers the activation of KRAS/MAPK signaling to increase YAP1 and downstream Slug expression, which are suppressed by an anti-VEGFR3 (VEGF receptor 3) peptide, a specific peptide targeting VEGFR3. The VEGF-C-induced migration, invasion and stemness of skin cancer cells are also abrogated by the anti-VEGFR3 peptide. Based on these data, we reveal the role of the VEGF-C/VEGFR3-mediated KRAS/MAPK-YAP1/Slug pathway in skin cancer progression and propose that the VEGF-C/VEGFR3 axis is a promising target for the anti-VEGFR3 peptide.

• Authors: Yu-Wen Yeh, Ching-Chia Cheng, Shu-Ting Yang, Chi-Feng Tseng, Ting-Yu Chang, Sin-Ying Tsai, Earl Fu, Chien-Ping Chiang, Li-Chuan Liao, Pei-Wen Tsai, Yung-Luen Yu, Jen-Liang Su
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 3 Pg. 5603-5618 (Jan 17 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 27901498 (Publication Type: Journal Article, Review)

Chemical References

• SNAI1 protein, human
• Snail Family Transcription Factors
• Vascular Endothelial Growth Factor C
• FLT4 protein, human
• Vascular Endothelial Growth Factor Receptor-3

Topics

• Cell Movement (physiology)
• Humans
• Neoplasm Invasiveness (pathology)
• Neoplastic Stem Cells (metabolism, pathology)
• Signal Transduction (physiology)
• Skin Neoplasms (metabolism, pathology)
• Snail Family Transcription Factors (metabolism)
• Vascular Endothelial Growth Factor C (metabolism)
• Vascular Endothelial Growth Factor Receptor-3 (metabolism)