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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES020137-01A1
Application #
8370816
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Tyson, Frederick L
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2012-09-01
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$350,402
Indirect Cost
$92,664
Name
Wayne State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Pharmacy
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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