title: Global gene expression changes in human urothelial cells exposed to low-level monomethylarsonous acid.
abstract: 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 50nM 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.
authors: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States. medeiros@pharmacy.arizona.edu
authors: Matthew
authors: M
authors: Medeiros
authors: Xinghui
authors: X
authors: Zheng
authors: Petr
authors: P
authors: Novak
authors: Shawn M
authors: SM
authors: Wnek
authors: Vivian
authors: V
authors: Chyan
authors: Claudia
authors: C
authors: Escudero-Lourdes
authors: A Jay
authors: AJ
authors: Gandolfi
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D004260:DNA Repair; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D040081:Protein Array Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000378:metabolism; D019459:Urothelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D009942:Organometallic Compounds; C406082:monomethylarsonous acid; D020928:Mitogen-Activated Protein Kinases