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

Aging (Albany NY). 2019 Aug 19;11(16):6273-6285. doi: 10.18632/aging.102187. Epub 2019 Aug 19.

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.

Keywords: angiogenesis; kindlin-2; mTOR/VEGFA; melanoma; prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Melanoma / metabolism*
  • Membrane Proteins / metabolism*
  • Mice, Nude
  • Neoplasm Proteins / metabolism*
  • Neoplasms, Experimental
  • Neovascularization, Pathologic / metabolism*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • FERMT3 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • MTOR protein, human
  • TOR Serine-Threonine Kinases