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Weiming Ouyang,^1,* Wenjing Luo,^1,2,* Dongyun Zhang,^1,* Jinlong Jian,¹ Qian Ma,¹ Jingxia Li,¹ Xianglin Shi,³ Jingyuan Chen,² Jimin Gao,⁴ and Chuanshu Huang¹

¹Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA; ²Department of Occupational and Environmental Health Sciences, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China; ³Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky, USA; ⁴Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, People's Republic of China

Abstract
Background: Long-term exposure of arsenite leads to human skin cancer. However, the exact mechanisms of arsenite-induced human skin carcinogenesis remain to be defined.

Objectives: In this study, we investigated the potential role of PI-3K/Akt/cyclin D1in the transformation of human keratinocytic cells upon arsenite exposure.

Methods: We used the soft agar assay to evaluate the cell transformation activity of arsenite exposure and the nude mice xenograft model to determine the tumorigenesis of arsenite-induced transformed cells. We used the dominant negative mutant and gene knockdown approaches to elucidate the signaling pathway involved in this process.

Results: Our results showed that repeated long-term exposure of HaCat cells to arsenite caused cell transformation, as indicated by anchorage-independent growth in soft agar. The tumorigenicity of these transformed cells was confirmed in nude mice. Treatment of cells with arsenite also induced significant activation of PI-3K and Akt, which was responsible for the anchorage-independent cell growth induced by arsenite exposure. Furthermore, our data also indicated that cyclin D1 is an important downstream molecule involved in PI-3K/Akt–mediated cell transformation upon arsenite exposure based on the facts that inhibition of cyclin D1 expression by dominant negative mutants of PI-3K, and Akt, or the knockdown of the cyclin D1 expression by its specific siRNA in the HaCat cells resulted in impairing of anchorage-independent growth of HaCat cells induced by arsenite.

Conclusion: Our results demonstrate that PI-3K/Akt–mediated cyclin D1 expression is at least one key event implicated in the arsenite human skin carcinogenic effect.

Key words: Akt, arsenite, cyclin D1, human keratinocyte, PI-3K. Environ Health Perspect 116:1–6 (2008) . doi:10.1289/ehp.10403 available via http://dx.doi.org/ [Online 5 October 2007]

Address correspondence to C. Huang, Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd., Tuxedo, NY 10987 USA. Telephone: (845) 731-3519. Fax: (845) 351-2320. E-mail: chuanshu@env.med.nyu.edu

*These authors contributed equally to the work.

This work was supported in part by grants from the National Institutes of Health (NIH) /National Cancer Institute R01 CA094964 (C.H.) , R01 CA112557 (C.H.) , R01 CA103180 (C.H.) , R01 CA119028 (X.S.) , NIH/National Institute of Environmental Health Sciences (NIEHS) R01 ES012451 (C.H.) , and NIEHS Center grant ES000260.

The authors declare they have no competing financial interests.

Received 24 April 2007 ; accepted 4 October 2007.