Regulation of motility, invasion, and metastatic potential of squamous cell carcinoma by 1α,25-dihydroxycholecalciferol

Cancer. 2013 Feb 1;119(3):563-74. doi: 10.1002/cncr.27531. Epub 2012 Jul 25.


Background: The active metabolite of vitamin D 1α,25-dihydroxycholecalciferol (1,25D(3) ) has exhibited broad-spectrum antitumor activity in xenograft animal models. However, its activity against metastatic disease has not been extensively investigated.

Methods: Squamous cell carcinoma (SCC) or 1,25D(3) -resistant variant SCC-DR cells were treated with 1,25D(3) . Actin organization was examined by immunofluorescence assay. Cell migration was assessed by "wound" healing and chemotactic migration assays. Cell invasion was assessed by a Matrigel-based invasion assay and in situ zymography. Matrix metalloproteinase 2 (MMP-2) and MMP-9 expression and secretion were examined by immunoblot analysis and an enzyme-linked immunosorbent assay, respectively. E-cadherin expression was assessed by flow cytometry, immunoblot analysis, and immunohistochemistry. Knockdown of E-cadherin was achieved by small interfering RNA. An experimental metastasis mouse model was created by intravenous injection of tumor cells; and lung tumor development in the mice was assessed by magnetic resonance imaging, gross observation, and histology.

Results: SCC cellular morphology and actin organization were altered by 10 nM 1,25D(3) . 1,25D(3) inhibited SCC cell motility and invasion, which were associated with reduced expression and secretion of MMP-2 and MMP-9, and 1,25D(3) promoted the expression of E-cadherin. These findings were not observed in SCC-DR cells. Knock down of E-cadherin rescued 1,25D(3) -inhibited cell migration. Intravenous injection of SCC or SCC-DR cells resulted in the establishment of extensive pulmonary lesions in saline-treated C3H mice. Treatment with 1,25D(3) resulted in a marked reduction in the formation of lung tumor colonies in mice that were injected with SCC cells, but not in mice that were injected with SCC-DR cells.

Conclusions: 1,25D(3) suppressed SCC cell motility, invasion, and metastasis, partially through the promotion of E-cadherin-mediated cell-cell adhesion.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism
  • Calcitriol / pharmacology*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / pathology*
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Shape / drug effects
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation, Neoplastic / drug effects
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology*
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred C3H
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation


  • Cadherins
  • Calcitriol