Molecular Mechanism of Arsenic Carcinogenesis

Thomas Jefferson University, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): 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.