Neuropilin-2 promotes tumourigenicity and metastasis in oesophageal squamous cell carcinoma through ERK-MAPK-ETV4-MMP-E-cadherin deregulation

J Pathol. 2016 Jul;239(3):309-19. doi: 10.1002/path.4728. Epub 2016 May 5.


Oesophageal squamous cell carcinoma (ESCC) is the most common histological subtype of oesophageal cancer. The disease is particularly prevalent in southern China. The incidence of the disease is on the rise and its overall survival rate remains dismal. Identification and characterization of better molecular markers for early detection and therapeutic targeting are urgently needed. Here, we report levels of transmembrane and soluble neuropilin-2 (NRP2) to be significantly up-regulated in ESCC, and to correlate positively with advanced tumour stage, lymph node metastasis, less favourable R category and worse overall patient survival. NRP2 up-regulation in ESCC was in part a result of gene amplification at chromosome 2q. NRP2 overexpression promoted clonogenicity, angiogenesis and metastasis in ESCC in vitro, while NRP2 silencing by lentiviral knockdown or neutralizing antibody resulted in a contrary effect. This observation was extended in vivo in animal models of subcutaneous tumourigenicity and tail vein metastasis. Mechanistically, overexpression of NRP2 induced expression of ERK MAP kinase and the transcription factor ETV4, leading to enhanced MMP-2 and MMP-9 activity and, as a consequence, suppression of E-cadherin. In summary, NRP2 promotes tumourigenesis and metastasis in ESCC through deregulation of ERK-MAPK-ETV4-MMP-E-cadherin signalling. NRP2 represents a potential diagnostic or prognostic biomarker and therapeutic target for ESCC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: ESCC; ETV4; NRP2; RNA-Seq; metastasis.

MeSH terms

  • Adenovirus E1A Proteins / genetics
  • Adenovirus E1A Proteins / metabolism*
  • Animals
  • Antigens, CD
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Carcinogenesis
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cohort Studies
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphatic Metastasis
  • MAP Kinase Signaling System / genetics*
  • Neuropilin-2 / genetics
  • Neuropilin-2 / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-ets
  • Transcriptome
  • Up-Regulation


  • Adenovirus E1A Proteins
  • Antigens, CD
  • Biomarkers, Tumor
  • CDH1 protein, human
  • Cadherins
  • ETV4 protein, human
  • Neuropilin-2
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • neuropilin-2, human