Up-regulated expression of zonula occludens protein-1 in human melanoma associates with N-cadherin and contributes to invasion and adhesion

Am J Pathol. 2005 May;166(5):1541-54. doi: 10.1016/S0002-9440(10)62370-X.


During the process of malignant transformation, nascent melanoma cells escape keratinocyte control through down-regulation of E-cadherin and instead communicate among themselves and with fibroblasts via N-cadherin-based cell-cell contacts. The zonula occludens (ZO) protein-1 is a membrane-associated component of both the tight and adherens junctions found at sites of cell-cell contact. In most cancers, levels of ZO-1 are typically down-regulated, leading to increased motility. Here we report the novel observation that ZO-1 expression is up-regulated in melanoma cells and is located at adherens junctions between melanoma cells and fibroblasts. Immunofluorescence and co-immunoprecipitation studies showed co-localization of ZO-1 with N-cadherin. Down-regulation of ZO-1 in melanoma cells through RNA interference produced marked changes in cell morphology--leading to a less-dendritic, more rounded phenotype. Consistent with a role in N-cadherin-based adhesion, RNAi-treated melanoma cells were less adherent and invasive when grown in a collagen gel. These data provide the first evidence that increased ZO-1 expression in melanoma contributes to the oncogenic behavior of this tumor and further illustrate that protein products of genes, such as ZO-1, can function in either a pro- or anti-oncogenic manner when expressed in different cellular contexts.

Publication types

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

MeSH terms

  • Adherens Junctions / metabolism
  • Cadherins / metabolism*
  • Cell Adhesion
  • Cell Shape
  • Cells, Cultured
  • Collagen
  • Down-Regulation
  • Fibroblasts / metabolism
  • Gels
  • Humans
  • Keratinocytes / metabolism
  • Melanoma / metabolism*
  • Melanoma / pathology*
  • Melanoma / physiopathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Neoplasm Invasiveness
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA Interference
  • RNA, Neoplasm / metabolism
  • Tissue Distribution
  • Tumor Cells, Cultured
  • Up-Regulation
  • Zonula Occludens-1 Protein


  • Cadherins
  • Gels
  • Membrane Proteins
  • Phosphoproteins
  • RNA, Neoplasm
  • TJP1 protein, human
  • Zonula Occludens-1 Protein
  • Collagen