Long-term human exposure to inorganic arsenic induces lung and other cancers. The molecular mechanisms of arsenic-induced carcinogenesis remain to be elucidated. Our preliminary studies show that arsenic increases reactive oxygen species (ROS) production, inhibits miR-199 and miR-148 expression, and increases ERBB2, PKM2, NF-kB, HIF-1 and IL-8 expression in lung epithelial cells. Arsenic treatment also induces cell transformation, tumor growth and angiogenesis. We hypothesize that arsenic suppresses miR-199/148 expression through the induction of NOX2, p47phox, ROS;and DNMT1 expression;and miR-199/148 downregulation regulates carcinogenesis (cell transformation, tumor growth, and angiogenesis) through targets: ERBB2 and PKM2/NF-:B. To test this hypothesis, three aims are proposed.
Aim 1 will investigate the mechanisms of arsenic in suppressing miR-199 and miR-148 expression through NOX2/p47phox/DNMT1 induction, ROS generation;and miR-199/148 downregulation in turn regulates ERBB2 expression and PKM2/NF-kB interaction. We will investigate: 1) whether arsenic suppresses miR-199 and miR-148 expression through the induction of NOX2, p47Phox, ROS, and DNMT1;2) whether arsenic induces ERBB2 and PKM2 expression by miR-199/148 downregulation;3) what regions of PKM2 bind with NF-kB p65 subunit for regulating IL-8 and HIF-1 expression.
Aim 2 will investigate the roles of miR-199/148 downregulation in inducing ERBB2 and PKM2/NF-kB expression for regulating cell transformation and tumor growth. We will determine: 1) whether arsenic induces cell transformation and tumor growth through ROS- and DNMT1-induced miR-199/148 downregulation;2) whether ERBB2 and PKM2 are key direct targets of miR-199/148 for regulating arsenic-induced transformation and tumor growth;and 3) whether PKM2/NF-:B interaction plays an important role.
Aim 3 will investigate the mechanisms of arsenic-induced angiogenesis through miR-199/148/ERBB2/PKM2/NF-kB axis for inducing HIF-1 and IL- 8 via paracrine effect using animal models. We will also determine whether secretion of IL-8 will induce tumor angiogenesis through functional IL-8 receptors in endothelial cells (paracrine effect) using chimeric tumor model. This proposed study would provide an important paradigm shift in understanding how miRNAs regulate arsenic-induced tumor growth and angiogenesis through ERBB2 and PKM2/NF-kB axis. Given the important roles of ERBB2, PKM2, NF-kB, HIF-1, and IL-8 in different types of cancers;the proposed studies would be important for future studies on mechanism-based prevention and treatment for arsenic-induced cancer as well as other human cancers.

Public Health Relevance

Environmental exposure to arsenic causes lung cancer. The present study will investigate new mechanism of arsenic in inducing carcinogenesis through microRNAs and several proto-oncogenes. The expected novel results will be important to understand new mechanism of arsenic carcinogenesis and to help develop new therapeutic and preventive strategies in the future.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Radiation Therapeutics and Biology Study Section (RTB)
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Thompson, Claudia L
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Thomas Jefferson University
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