Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway

Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 04/2012; 262(1):11-21. DOI: 10.1016/j.taap.2012.04.014
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Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealed that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of β-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of β-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited β-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggests that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/β-catenin signaling pathway.

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Available from: Xianglin Shi, Oct 07, 2015
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    • "A number of reports revealed that inorganic arsenic, especially the trivalent arsenic (As 3+ ), may induce excessive generation of the reactive oxygen species (ROS) in mammalian cells (Chou et al., 2004; Hei et al., 1998; Wang et al., 2013; Zhang et al., 2011). ROS were able to cause genetic mutation and cancer through the mechanism of DNA damage, activation of the oncogenic kinases(Wang et al., 2012), or oxidation of the important lipids and proteins to inactivate DNA repairing machineries , such as poly(ADP ribose) polymerase (PARP)-1 (Hubaux et al., 2012; Wang et al., 2013). There are several cellular sources of ROS induced by As 3+ . "
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    • "The levels of superoxide (O2−) and peroxide (H2O2) were measured in larval hemocytes using dihydroethidium (DHE; Invitrogen, USA) and 2′, 7′-dihydrofluorescein diacetate (H2DCFDA) respectively following the methods reported earlier [9], [25] with minor modifications. Briefly, isolated hemocytes were incubated with respective dyes at the final concentration of 10 µM for 1 h in dark at 24±1°C. "
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