title: 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.affiliation: Division of Dermatology, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei 10581, Taiwan.|Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
authors.forename: Ching-Chia
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Yang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
authors.forename: Chi-Feng
authors.initials: CF
authors.lastname: Tseng
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Chang
authors.affiliation: Department of Biotechnology, Asia University, Taichung 41354, Taiwan.
authors.forename: Sin-Ying
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Department of Periodontology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
authors.forename: Earl
authors.initials: E
authors.lastname: Fu
authors.affiliation: Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Chiang
authors.affiliation: Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu 30062, Taiwan.
authors.forename: Li-Chuan
authors.initials: LC
authors.lastname: Liao
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Tsai
authors.affiliation: Department of Biotechnology, Asia University, Taichung 41354, Taiwan.|Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.|Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan.
authors.forename: Yung-Luen
authors.initials: YL
authors.lastname: Yu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.|Department of Biotechnology, Asia University, Taichung 41354, Taiwan.|Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.|Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan.
authors.forename: Jen-Liang
authors.initials: JL
authors.lastname: Su
mesh_terms: D002465:Cell Movement / Q000502:physiology; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D042582:Vascular Endothelial Growth Factor C; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: VEGF-C; YAP1; cancer stemness; metastasis; skin cancer