Access Type

Open Access Dissertation

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmaceutical Sciences

First Advisor

Fei Chen

Abstract

Arsenic is a well-recognized environmental health threat with the capability of inducing a number of human diseases, including cancer. The aim of this dissertation is to unveil the mechanisms underlying the carcinogenic activities of environmental arsenic. The biological functions of arsenic had been studied for decades. However, there are still many questions that remain to be fully answered, such as whether and how arsenic contributes to the epigenetic regulations and migration or metastasis control of the cancer cells. In this regard, we focused our attention on both histone modifications and miRNA regulations in the arsenic-induced malignant transformation of the cells, and tried to establish the signaling cascades that mediate arsenic-induced transformation. Furthermore, we investigated the downstream functional pathways related to malignancy through biochemical and proteomics analyses. Based on the results from the first specific aim, we had demonstrated that long term treatment of the cells with arsenic at concentrations that are comparable to environment arsenic exposure is able to induce EZH2 phosphorylation that facilitates its cytoplasmic localization, and the expression of c-myc. Meanwhile, we also noted that long-term treatment of the cells with arsenic induces expression of miR-214 and miR-199a along with a metabolic reprogramming of the cells from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis (Warburg Effects). In the second specific aim, we further identified interaction of mdig and Filamin A phosphorylation that is involved in cell motility and migration induced by arsenic. Collectively, our studies on the novel pathways induced by arsenic provide new insights for the carcinogenetic mechanism of arsenic and shed light on the prevention and promising therapeutic strategies for human cancers that are associated with environmental arsenic exposure.

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