N-myc downstream-regulated gene 1 downregulates cell proliferation, invasiveness, and tumorigenesis in human oral squamous cell carcinoma

Cancer Lett. 2014 Dec 28;355(2):242-52. doi: 10.1016/j.canlet.2014.08.035. Epub 2014 Sep 10.

Abstract

Oral squamous cell carcinoma (OSCC) is the most common phenotype of oral cancer. N-myc downstream regulated gene 1 (NDRG1) is a modulator for cell proliferation, differentiation, and invasion. The role and function of NDRG1 in OSCC cells remain inconclusive. The (3)H-thymidine incorporation and in vitro matrigel invasion assays revealed NDRG1-knockdown significantly enhanced OSCC cell proliferation and invasion. Overexpressed NDRG1 arrested the cell cycle at the S-phase, thus attenuated cell proliferation in OECM-1 cells. The NDRG1-knockdown enhanced tumorigenesis of OECM-1 cells in the xenograft animal model. Western-blot and zymographic assays revealed that NDRG1 downregulated the gelatinase activities and protein levels of metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9). NDRG1 modulated epithelial-mesenchymal transition (EMT) through upregulation of the E-cadherin expression, but downregulation of the N-cadherin, Vimentin, Snail-1, and Slug. Immunofluorescence staining indicated knockdown of NDRG1 enhanced F-actin expression and polymerization. Our results indicated NDRG1 attenuated OSCC cell growth in vitro and in vivo. The downregulation of EMT, MMP-2, and MMP-9 may explain the role of anti-invasion of NDRG1 in human OSCC cells. The experiments recognize that NDRG1 is an antitumor gene in OSCC cells.

Keywords: EMT; Invasion; MMP-2; MMP-9; NDRG1; OSCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology*
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Male
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice, Inbred BALB C
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / metabolism
  • Mouth Neoplasms / pathology*
  • Neoplasm Invasiveness
  • Squamous Cell Carcinoma of Head and Neck
  • Up-Regulation

Substances

  • Cadherins
  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • N-myc downstream-regulated gene 1 protein
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9