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

// Yu-Wen Yeh 1, 2 , Ching-Chia Cheng 3, 4 , Shu-Ting Yang 4 , Chi-Feng Tseng 4 , Ting-Yu Chang 4 , Sin-Ying Tsai 5 , Earl Fu 6 , Chien-Ping Chiang 7 , Li-Chuan Liao 8 , Pei-Wen Tsai 9 , Yung-Luen Yu 5, 10, 11 , Jen-Liang Su 4, 5, 10, 11 1 Division of Dermatology, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei 10581, Taiwan 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan 3 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan 4 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan 5 Department of Biotechnology, Asia University, Taichung 41354, Taiwan 6 Department of Periodontology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan 7 Department of Dermatology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan 8 Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu 30062, Taiwan 9 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan 10 Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan 11 Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan Correspondence to: Jen-Liang Su, email: jlsu@nhri.org.tw Yung-Luen Yu, email: ylyu@mail.cmu.edu.tw Keywords: VEGF-C, YAP1, metastasis, cancer stemness, skin cancer Received: August 08, 2016 Accepted: November 07, 2016 Published: November 25, 2016 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.