S100A8/A9 regulates MMP-2 expression and invasion and migration by carcinoma cells

Int J Biochem Cell Biol. 2014 Oct:55:279-87. doi: 10.1016/j.biocel.2014.09.007. Epub 2014 Sep 16.

Abstract

Intracellular calprotectin (S100A8/A9) functions in the control of the cell cycle checkpoint at G2/M. Dysregulation of S100A8/A9 appears to cause loss of the checkpoint, which frequently characterizes head and neck squamous cell carcinoma (HNSCC). In the present study, we analyzed carcinoma cells for other S100A8/A9-directed changes in malignant phenotype. Using a S100A8/A9-negative human carcinoma cell line (KB), transfection to express S100A8 and S100A9 caused selective down-regulation of MMP-2 and inhibited in vitro invasion and migration. Conversely, silencing of endogenous S100A8 and S100A9 expression in TR146 cells, a well-differentiated HNSCC cell line, increased MMP-2 activity and in vitro invasion and migration. When MMP-2 expression was silenced, cells appeared to assume a less malignant phenotype. To more closely model the architecture of cell growth in vivo, cells were grown in a 3D collagen substrate, which was compared to 2D. Growth on 3D substrates caused greater MMP-2 expression. Whereas hypermethylation of CpG islands occurs frequently in HNSCC, S100A8/A9-dependent regulation of MMP-2 could not be explained by modification of the upstream promoters of MMP2 or TIMP2. Collectively, these results suggest that intracellular S100A8/A9 contributes to the cancer cell phenotype by modulating MMP-2 expression and activity to regulate cell migration and mobility.

Keywords: Calprotectin; Carcinoma; In vitro; Matrix metalloproteinase-2; S100A8/A9.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Calgranulin A / genetics*
  • Calgranulin A / metabolism
  • Calgranulin B / genetics*
  • Calgranulin B / metabolism
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Carcinoma / pathology
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Movement / genetics*
  • Collagen / metabolism
  • CpG Islands / genetics
  • DNA Methylation
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MCF-7 Cells
  • Matrix Metalloproteinase 2 / genetics*
  • Matrix Metalloproteinase 2 / metabolism
  • Neoplasm Invasiveness
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Calgranulin A
  • Calgranulin B
  • Collagen
  • Matrix Metalloproteinase 2