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Research Paper|Volume 11, Issue 16|pp 6273—6285

Elevated kindlin-2 promotes tumour progression and angiogenesis through the mTOR/VEGFA pathway in melanoma

Chuan-Yuan Wei1,2, Meng-Xuan Zhu3, Peng-Fei Zhang4, Xuan Yang2, Lu Wang1, Jiang-Hui Ying1, Wen-Jie Luan1, Cheng Chen1, Jia-Qi Liu1, Ming Zhu1, Yan-wen Yang1, Zi-Hao Feng1, Fa-Zhi Qi1, Jian-Ying Gu1
  • 1Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
  • 2Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, P.R. China
  • 3Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, P.R. China
  • 4Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200032, P.R. China
* Equal contribution
Received: May 4, 2019Accepted: August 10, 2019Published: August 19, 2019
https://doi.org/10.18632/aging.102187

Copyright © 2019 Wei et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: In our previous study, kindlin-2 promoted skin wound healing and decreased the permeability of neovascularization during angiogenesis. Herein, we explored the biological function and underlying mechanism of kindlin-2 in cutaneous melanoma.

Methods and Results: Through a series of in vitro assays, we found that high levels of kindlin-2 promoted migration and invasion of melanoma cells without influencing cell proliferation. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analyses showed that upregulated kindlin-2 promoted the cellular epithelial-mesenchymal transition (EMT). Importantly, we found that melanoma cells overexpressing kindlin-2 promoted angiogenesis and VEGFA secretion in vitro and facilitated tumour growth and lung metastasis in vivo. To unveil the underlying mechanism, we conducted Next-generation sequencing (NGS) and differential expression analyses. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that overlapping differentially expressed genes (DEGs) were primarily enriched in the TGF-β, mTOR and VEGF signalling pathways. Then, we confirmed that the mTOR/VEGFA pathway was activated during the process of kindlin-2-induced melanoma progression and angiogenesis. Moreover, we demonstrated that kindlin-2 was significantly overexpressed in clinical melanoma samples and that a high level of kindlin-2 predicted a poor prognosis.

Conclusions: Taken together, these findings showed that kindlin-2 promotes angiogenesis and tumour progression via the mTOR/VEGFA pathway.