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R. Dror, T. Meir, X. Yu, J. Qian, I. Simon, J. Pe’er, I. Chowers; Characterizing Molecular Pathways Which Underlie the Development of Metastases From Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4772.
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© ARVO (1962-2015); The Authors (2016-present)
Uveal melanoma (UM) is associated with death due to the development of systemic metastases in about 50% of patients. We aim to obtain insight into the molecular pathways which underlie the development of metastases from UM in order to identify potential novel therapeutic targets for this disease.
Bioinformatics was applied on a microarray dataset containing gene expression patterns from seven primary UM and seven liver metastases from UM, respectively. Gene expression patterns were compared across UM metastases and variety of normal and malignant tissues. Transcription factors which may regulate expression of metastases associated genes were identified using two complementary bioinformatics approaches. Results were validated using real time quantitative RT-PCR (QPCR) and immunohistochemistry (IHC).
Gene expression pattern of liver metastases from UM shared similarities with expression pattern of normal liver tissue. Several transcription factors which potentially regulate expression of metastases associated genes were identified among them NFkB. NFkB2 showed higher mRNA levels in UM metastases compared with the primary tumor according to microarray analysis (false discovery rate = 5%, significance analysis for microarrays) and QPCR (P = 0.03, t-test), and higher protein levels according to IHC (P = 0.002, t-test). Altered mRNA levels of additional members of the NFkB family and of genes associated with NFkB signal transduction pathways among them NFkB1, RelA, RelB, GADD45ß, HHIP, CSF2 and CDK4 were also detected by microarray and QPCR. CDK4 also showed altered protein levels according to IHC (P = 0.01, t-test).
Gene expression similarities between liver metastases from UM and normal liver tissue may either be related to the predilection of such metastases to develop in liver or, alternatively, may be secondary to the effect of liver microenvironment. Several members of the NFkB family show altered expression in liver metastases from UM. Based on their known function in other malignancies, this pathway may be important for the growth of UM metastases.
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