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M. H. Abdel-Rahman, A. A. Agour, F. H. Davidorf; A Complex Role of NBS1 Gene in the Tumorogenesis of Uveal Melanomas. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1501.
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Nijmegen breakage syndrome (NBS) gene product, NBS1 (p95), is a part of the hMre11 complex, a central player associated with double strand break repair. NBS1 is largely considered as a tumor suppressor gene. A previous report has shown an association between overexpression of NBS1 and aggressive uveal melanomas. However, the molecular mechanism of NBS1 in the tumorogenesis of uveal melanomas has not been addressed. In this study we investigate such mechanism.
NBS1 and phospho-AKT expression in primary uveal melanomas was studied using immunohistochemistry in 91 primary uveal melanomas. Expression of NBS1 in ten different normal tissues, as well, as in two tumor cell lines showing amplification in the NBS1 gene were used as controls for efficiency of immunohistochemistry. The intensity of staining was assessed in both tumors and normal tissue (retina and choroid). The frequency of gains/amplification in chromosomal bands 8q21 (chromosomal location of NBS1) was studied by either conventional and/or molecular cytogenetics in a subset of tumors.
Over-expression of NBS1 protein was detected in 28/91 (30.1%) tumors, moderate expression in 35/91 (38.5%) tumors, while absent or weak expression in 28/91 (30.1%) tumors. The expression of NBS1 correlated strongly with the expression of phospho AKT (r=0.76). However, the expression didn’t correlate very strongly with the status of 8q21 region. High expression of NBS1 was detected in the majority of normal tissues, as well as, the choroid and retina of the tumors. The expression of NBS1 in the tumors was weaker (50%) or equal (27.8%) to the retina in the majority of the tumors.
Our study suggests a complex role of NBS1 gene in the tumorogenesis of uveal melanomas. The association of normal or increased NBS1 expression with tumor aggressiveness could be due to its regulation of cell survival/apoptosis through its regulation of the level of pAKT. However, in tumors treated with radiation the loss of NBS1 expression may confer an increased sensitivity to radiation and hence could be utilized as a good prognostic marker.
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