Up-regulated expression of zonula occludens protein-1 in human melanoma associates with N-cadherin and contributes to invasion and adhesion.
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.
Smalley
Keiran S M
KS
Wistar Institute, 3601 Spruce St., Philadelphia, Pennsylvania 19104, USA.
Brafford
Patricia
P
Haass
Nikolas K
NK
Brandner
Johanna M
JM
Brown
Eric
E
Herlyn
Meenhard
M
D022005:Adherens Junctions / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D048430:Cell Shape; D002478:Cells, Cultured; D003094:Collagen; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005782:Gels; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012334:RNA, Neoplasm / Q000378:metabolism; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D062826:Zonula Occludens-1 Protein
D015820:Cadherins; D005782:Gels; D008565:Membrane Proteins; D010750:Phosphoproteins; D012334:RNA, Neoplasm; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D003094:Collagen