Chronic arsenic exposure through drinking water is a global health issue, affecting more than 200 million people. Arsenic is a group I human carcinogen and causes chromosomal instability (CIN). Arsenic exposure is the second most cause of skin cancer after UV radiation. MiR-186 is overexpressed in arsenic-induced squamous cell carcinoma relative to premalignant hyperkeratosis. Predicted targets of miR-186 are cell cycle regulators. Thus, we hypothesize that miR-186 overexpression drives

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... t transformation of HaCaT cells by induction of CIN. Stable clones of HaCaT transfected with pEP-miR-186 expression vector or empty vector were maintained under puromycin selection were exposed to 0 or 100 nM NaAsO2 and cultured for 29 weeks. HaCaT overexpressing miR-186 and exposed to NaAsO2 showed growth ability in agar at 12 weeks and increased CIN in contrast to unexposed vector control cells. These cells also undergo epithelial to mesenchymal transition and form colonies in agar at 29 weeks. These results suggest that miR-186 overexpression exacerbates the arsenite-induced CIN and potentially is associated with accelerated skin carcinogenesis. CHAPTER 1: INTRODUCTION 1.1 Arsenic: An ambiguous and ubiquitous toxic metalloid Heavy metals are ubiquitous in the environment and heavy metal-induced environmental pollution is a global health hazard. Arsenic is a prevalent natural pollutant and the 20 th most common element in the earth's crust (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans., 2012). It is ranked first on the Agency for Toxic Substances and Disease Registry (ATSDR) Substance Priority List for more than 20 years (ATSDR, 2017). Arsenic is a toxic metalloid and acknowledged carcinogen. In 1973, arsenic was classified as a group I human carcinogen by the International Agency for Research on Cancer (IARC) [2]. Arsenic is also clastogenic and it causes chromosomal instability (CIN) both in vitro and in vivo [3]. CIN is a hallmark of carcinogenesis, and it is associated with poor prognosis, metastasis, and therapeutic resistance [4]. The molecular mechanism by which arsenic induces CIN-mediated carcinogenesis is yet to be delineated [5] . Arsenic has also an atherogenic potential according to epidemiologic studies that have shown an association between elevated arsenic levels in drinking water and an increased risk of atherosclerosis and cardiovascular diseases [6] [7]. It is also reported that sodium arsenate induces developmental malformations in a variety of experimental animals after subjecting mothers to administration of teratogenic levels of arsenate [8] . Arsenic has been used since ancient times, both as a poison and a medicine. It is a component of Chinese, Tibetan, Vietnamese, and Indian traditional medicines [9] . Arsenicals also are still used to treat some tropical diseases [9] . It is tasteless, colorless,