Global gene expression changes in human urothelial cells exposed to low-level monomethylarsonous acid
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Bladder cancer has been associated with chronic arsenic exposure. Monomethylarsonous acid [MMA(III)] is a metabolite of inorganic arsenic and has been shown to transform an immortalized urothelial cell line (UROtsa) at concentrations 20-fold less than arsenite. MMA(III) was used as a model arsenical to examine the mechanisms of arsenical-induced transformation of urothelium. A microarray analysis was performed to assess the transcriptional changes in UROtsa during the critical window of chronic 50. nM MMA(III) exposure that leads to transformation at 3 months of exposure. The analysis revealed only minor changes in gene expression at 1 and 2 months of exposure, contrasting with substantial changes observed at 3 months of exposure. The gene expression changes at 3 months were analyzed showing distinct alterations in biological processes and pathways such as a response to oxidative stress, enhanced cell proliferation, anti-apoptosis, MAPK signaling, as well as inflammation. Twelve genes selected as markers of these particular biological processes were used to validate the microarray and these genes showed a time-dependent changes at 1 and 2 months of exposure, with the most substantial changes occurring at 3 months of exposure. These results indicate that there is a strong association between the acquired phenotypic changes that occur with chronic MMA(III) exposure and the observed gene expression patterns that are indicative of a malignant transformation. Although the substantial changes that occur at 3 months of exposure may be a consequence of transformation, there are common occurrences of altered biological processes between the first 2 months of exposure and the third, which may be pivotal in driving transformation. © 2011.
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Arsenic; Bladder cancer; Gene expression; Monomethylarsonous acid; UROtsa arsenic; mitogen activated protein kinase 1; monomethylarsonous acid; toxin; unclassified drug; apoptosis; article; biological phenomena and functions concerning the entire organism; bladder cancer; cancer cell culture; cell proliferation; cell transformation; drug exposure; gene; gene expression; genetic marker; human; human cell; human tissue; malignant transformation; microarray analysis; oxidative stress; phenotypic variation; priority journal; transitional cell carcinoma; urethritis; Apoptosis Regulatory Proteins; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; DNA Repair; Extracellular Matrix; Gene Expression; Gene Expression Profiling; Humans; Inflammation; Mitogen-Activated Protein Kinases; Organometallic Compounds; Oxidative Stress; Protein Array Analysis; Real-Time Polymerase Chain Reaction; Signal Transduction; Tumor Markers, Biological; Urinary Bladder Neoplasms; Urothelium
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