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Tiffany L. Wang, Frederick H. Davidorf, Mohamed H. Abdel-Rahman; The Role of Programmed Cell Death 4 in the Pathogenesis of Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3339.
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Programmed cell death 4 (PDCD4) is a tumor suppressor gene that was originally identified as a gene up-regulated during apoptosis. Loss of tumor suppressor function of PDCD4 has been described in several human malignancies including lung, colon, breast, pancreas, and ovary. However, its role is not clear in the pathogenesis of uveal melanoma (UM). The aim of this study was to determine the frequency of loss of PDCD4 expression in UM tumors, to explore the potential molecular mechanism associated with decreased PDCD4 expression in UM, and to determine the potential value of PDCD4 as a therapeutic target for treatment of UM.
Using expression profiling we identified decreased expression of PDCD4 in 75% (6/8) of uveal melanomas. We then studied 28 UM tumor samples, 2 choroids, and 5 cell lines, and these samples were assessed for RNA expression of PDCD4, miR-21 (a potential regulator of PDCD4), TIMP2, and CDH1 (two downstream targets of PDCD4 implicated in tumorigenesis) using quantitative real-time PCR. In addition, protein expression of PDCD4 was assessed using Western blot analysis. Finally, two UM cell lines, C918 and OCM-3, which exhibited low baseline levels of PDCD4 protein in preliminary Western blotting analyses, were treated with various concentrations of a selective PDCD4 activator.
The UM patients ranged from ages 27-83, with a median age of 59.5 years. Thirty-nine percent (11/28) of UM tumors were metastatic, and 61% (17/28) were non-metastatic. Forty-three percent (12/28) of UM tumors had decreased PDCD4 expression, and 75% (15/20) showed decreased miR-21 expression. Our quantitative real-time PCR results validated the previous expression profiling results, and suggest that PDCD4 is regulated by other factor(s) in addition to miR-21, and the downstream targets TIMP2 and CDH1 may be differentially regulated by PDCD4 as well. Finally, PDCD4 activation was shown to selectively inhibit cell proliferation in uveal melanomas with decreased PDCD4 expression.
This study is the first report regarding the potential role of PDCD4 in UM pathology, and suggests that selective PDCD4 activation may be a potential therapeutic target for the treatment of UM.
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