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(American Journal of Pathology. 2005;166:1541-1554.)
© 2005 American Society for Investigative Pathology

Up-Regulated Expression of Zonula Occludens Protein-1 in Human Melanoma Associates with N-Cadherin and Contributes to Invasion and Adhesion

Keiran S.M. Smalley^*, Patricia Brafford^*, Nikolas K. Haass^*, Johanna M. Brandner, Eric Brown and Meenhard Herlyn^*

From the Wistar Institute,^* Philadelphia, Pennsylvania; the Abramson Family Cancer Research Institute, Abramson Cancer Center at the University of Pennsylvania, Philadelphia, Pennsylvania; and the Department of Dermatology and Venerology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

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.

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