PINCH-2 presents functional copy number variation and suppresses migration of colon cancer cells by paracrine activity

Int J Cancer. 2015 May 15;136(10):2273-83. doi: 10.1002/ijc.29273. Epub 2014 Oct 30.

Abstract

In recent years, characterization of cancer and its environment has become necessary. However, studies of the cancer microenvironment remain insufficient. Copy number variations (CNVs) occur in 40% of cancer-related genes, but few studies have reported the correlation between CNVs in morphologically normal tissues adjacent to cancer and cancer progression. In this study, we evaluated cancer cell migration and invasion according to the genetic differences between cancer tissues and their surrounding normal tissues. To study the field cancerization effect, we screened 89 systemic metastasis-related CNVs from morphologically normal tissues adjacent to colon cancers. Among these CNVs, LIM and senescent cell antigen-like domain 2 (PINCH-2) showed copy number amplification and upregulation of mRNA in the nonrelapsed group compared to the systemic relapse group. PINCH-2 expression in colon cancer cells was lower than that in normal epithelial colon cells at both the protein and mRNA levels. Suppression of PINCH-2 resulted in decreased formation of the PINCH-2-IPP (PINCH-2, integrin-linked kinase and α-parvin) complex and reciprocally increased formation of the PINCH-1-IPP complex. Although PINCH-2 expression of survival pathway-related proteins (Akt and phospho-Akt) did not change upon suppression of PINCH-2 expression, cell migration-related proteins [matrix-metalloproteinase (MMP)-9 and -11] were upregulated through autocrine and paracrine activation. Thus, PINCH-2 participates in decreased systemic recurrence by competitively regulating IPP complex formation with PINCH-1, thereby suppressing autocrine and paracrine effects on motility in colon cancer. This genetic change in morphologically normal tissue suggests a field cancerization effect of the tumor microenvironment in cancer progression.

Keywords: IPP complex; PINCH-2; Systemic metastasis; array-CGH; colon cancer; copy number variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cell Line
  • Cell Movement
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Cytoskeletal Proteins / metabolism
  • DNA Copy Number Variations*
  • Female
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • LIM Domain Proteins / genetics*
  • LIM Domain Proteins / metabolism*
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Neoplasm Metastasis
  • Paracrine Communication*
  • Signal Transduction
  • Up-Regulation

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • IPP protein, human
  • LIM Domain Proteins
  • LIMS1 protein, human
  • LIMS2 protein, human
  • Membrane Proteins