Overexpression of the Promigratory and Prometastatic PTK7 Receptor Is Associated with an Adverse Clinical Outcome in Colorectal Cancer

PLoS One. 2015 May 11;10(5):e0123768. doi: 10.1371/journal.pone.0123768. eCollection 2015.

Abstract

Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules / genetics*
  • Cell Adhesion Molecules / metabolism
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality*
  • Colorectal Neoplasms / pathology
  • Disease Models, Animal
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Expression*
  • Heterografts
  • Humans
  • Male
  • Melanoma, Experimental
  • Mice
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Prognosis
  • RNA, Small Interfering / genetics
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Tumor Burden / genetics
  • Up-Regulation

Substances

  • Cell Adhesion Molecules
  • RNA, Small Interfering
  • PTK7 protein, human
  • Receptor Protein-Tyrosine Kinases

Grant support

This work was supported by La Ligue Nationale Contre le Cancer (Label Ligue JPB) http://www.ligue-cancer.net/, Fondation pour la Recherche Médicale (ACL) http://www.frm.org/, Region PACA (SM) http://www.regionpaca.fr/, SIRIC (INCa-DGOS-Inserm 6038) http://www.oncopaca.org/fr/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.