A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing

Elife. 2019 Mar 4:8:e44305. doi: 10.7554/eLife.44305.

Abstract

The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.

Keywords: Angiogenesis; L1CAM; NOVA2; Ovarian Cancer; atermative splicing; cancer biology; cell biology; human; mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Angiogenic Proteins / metabolism*
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Humans
  • Nerve Tissue Proteins / metabolism*
  • Neural Cell Adhesion Molecule L1 / metabolism*
  • Neuro-Oncological Ventral Antigen
  • Protein Isoforms / metabolism*
  • RNA-Binding Proteins / metabolism*

Substances

  • Angiogenic Proteins
  • L1CAM protein, human
  • NOVA2 protein, human
  • Nerve Tissue Proteins
  • Neural Cell Adhesion Molecule L1
  • Neuro-Oncological Ventral Antigen
  • Protein Isoforms
  • RNA-Binding Proteins