Our previous research has clearly demonstrated that trivalent arsenic (As3+) can induce cell transformation. The goal of this application is to determine the role of miR-190 in As3+-induced malignant transformation of the bronchial epithelial cells and the tumorigenesis of the lung. Major emphasis will be on the ROS- and Erk- mediated expression of miR-190 and the miR-190-dependent Akt activation and tumorigenesis. Our preliminary data have shown that (a) As3+ induces miR-190 generation in the human bronchial epithelial cell line, BEAS-2B, and human small airway epithelial cell line, SAEC, in a manner of both dose- and time- dependent; (b) MiR-190 mediates As3+-induced Akt activation by down-regulating the synthesis of PHLPP, an endogenous inhibitor of Akt signaling and a tumor suppressor; and (c) overexpression of miR-190 causes cell transformation. Based on these preliminary studies, we hypothesize that As3+-induced miR-190 is responsible for the sustained Akt activation, followed by cell transformation and consequently, the tumorigenesis. To test this hypothesis, three specific aims are proposed:
Specific Aim 1 will investigate how As3+ induces miR-190 in BEAS-2B and SAEC cell lines. We will focus on the regulation of both transcription and maturation of the precursor miR-190 by Erk, a key member of mitogen-activated protein kinase (MAPK) family, in the cells treated with As3+, Specific Aim 2 will determine the role of As3+-induced reactive oxygen species (ROS) on the activation of Erk and miR-190 production by As3+. We will identify each of the reactive oxygen species induced by As3+, and determine the sources of As3+-induced ROS that activate Erk and induce miR-190;
Specific Aim 3 will use overexpression and orthotopic tumorigenesis strategies to study the role of miR-190, ROS, Erk, and Akt in As3+-induced carcinogenesis by overexpressing miR-190, the antioxidant enzymes, and shRNA- mediated silencing of Erk or Akt in the human bronchial epithelial cells. We will use stable transfectants and determine the effects of overexpressing miR-190, antioxidant enzymes, and Erk or Akt silencing on either basal or As3+-induced cell transformation and carcinogenesis by assays of anchorage-independent growth in soft agar (colony formation) and inoculation of the cells in the lung of nude mice. The completion of this project will establish the mechanism of As3+-induced miR-190 generation and its role in As3+ carcinogenesis.
Environmental exposure of arsenic, especially the trivalent form arsenic, has long been a major public health concern. The present study will investigate the mechanism of arsenic-induced carcinogenesis by testing the hypothesis that arsenic-induced microRNA-190 is responsible for the malignant transformation and tumorigenesis of the cells. The long-term goals are to understand molecular mechanism of arsenic-induced carcinogenesis and to identify biomarkers for developing early detection, intervention and prevention strategies.
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