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Transcriptional Modulation of the ERK1/2 MAPK and NF-kB pathways in Human Urothelial cells after trivalent arsenical exposure: Implications for urinary bladder cancer
Citation:
Bailey, K. A., K. WALLACE, L. Smeester, S. Y. THAI, D. Wolf, S. W. Edwards, AND R. C. Fry. Transcriptional Modulation of the ERK1/2 MAPK and NF-kB pathways in Human Urothelial cells after trivalent arsenical exposure: Implications for urinary bladder cancer. CANCER RESEARCH. Australian Cancer Society, Sydney New South Wales, Australia, 1:57-68, (2012).
Impact/Purpose:
This work is to show the early changes in the signaling pathways that are caused by arsenic treatment in human bladder cell line (UROtsa)
Description:
Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk ofurinary bladder (DB) cancers in humans. Rodent models administered particular arsenicals have indicated urothelial necrosis followed by regenerative proliferation is a likely mode of action (MOA) of As-mediated DB carcinogenesis. However, the exact mechanisms involved in As-mediated toxicity and which As metabolite(s) elicit these toxic effects remain largely unknown. Experimental evidence suggests three trivalent arsenicals, iAs (arsenite; iAslll) and two of its urinary metabolites, monomethylarsonous acid (MMAlll) and dimethylarsinous acid (DMAIII) are possible proximate DB carcinogens. In this study, we used a transcriptomics approach to examine perturbed molecular pathways in a human urothelial cell line (DROtsa) after acute iAsIIl, MMAIII and DMAIII exposure in an effort to identify processes that may be involved in the early stages of As-mediated DB carcinogenesis. The relative transcriptional response was MMAIII>DMAIII and very little response from iAsIII. MMAIII and DMAIII exposure elicited different transcriptional profiles. However, the most significant perturbed processes in both groups included genes associated with cancer, cellular growth and development, cellular metabolism and cell death. Genes and networks implicated in DB cancer development were perturbed by both MMAIII and DMAIII, including ERK1/2 MAPK and NF-KB-containing molecular networks and the induction of pro-inflammatory and/or pro-growth genes (e.g. HBEGF, ILiA, IL8, MIF, PTGSi). Our results indicate that pro-carcinogenic transcriptional responses are elicited by both MMAIII and DMAIII in human urothelial cells and suggest ERK1/2-MAPK and NF-KB signaling may be important early events in As-mediated UB carcinogenesis.