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A. Jayagopal, J.-L. Yang, F. R. Haselton, M. S. Chang; Tight Junction-Associated Control of Proliferation in Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):868.
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Purpose : The underlying mechanisms governing the proliferation of uveal melanoma remain unclear. Tight junctions regulate cell-cell communication, and are involved in contact-mediated inhibition of cell proliferation. In this study, we investigated the role of tight junctions associated signaling in the proliferation of uveal melanoma.Methods :Human uveal melanoma cell lines were engineered to overexpress blood vessel epicardial substance (Bves), a regulator of tight junction formation. Basic cell behavior was investigated, including proliferation, cell cycle progression, invasion, and motility. The expression of proteins critical for cell cycle progression or inhibition was quantified. A reporter assay was used to quantify the function zonula occludens nucleic acid binding protein (ZONAB), a transcription factor associated with tight junctions which has been demonstrated to up regulate genes controlling cellular proliferation. Confocal microscopy was used to study ZONAB localization within uveal melanoma cell lines under normal conditions and under Bves overexpression.Results :Overexpression of the tight junction molecule Bves was shown to reduce cell proliferation in two and three dimensions, through expression of cell cycle inhibitory proteins, and through alteration of ZONAB localization within the cell. Invasion and motility were inhibited in cell lines overexpressing Bves. ZONAB activity was decreased under conditions of Bves overexpression. Immunofluorescence analysis revealed that ZONAB localization was restricted to the cytoplasm, as opposed to its nuclear localization in wild type uveal melanoma cell lines, suggesting that tight junctions may alter trafficking of the transcription factor.Conclusions :Tight junction proteins are involved in the proliferation of uveal melanoma, through cell signaling associations with cell cycle proteins and the transcription factor ZONAB. This pathway may represent potent therapeutic opportunities in management of uveal melanoma.
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