Arsenic is a well-studied human carcinogen. The mechanism by which arsenic induces cancer, however, is not well understood. It is known that as a general stress inducer, arsenic can activate kinases leading to the over activation of transcription factors including JNK and NF-kB. These transcription factors are known to regulate the expression of early response genes, and likely to regulate miRNAs. The expression of miRNAs is often altered in cancer and other proliferative disorders. It is highly probable then that miRNAs whose expression are altered by arsenic will play a significant role in carcinogenesis. To test this hypothesis, we investigated in-depth the role of arsenic in the transcriptional regulation of the miRNAs, determined targets of these miRNAs which cause carcinogenesis, and studied the overall cellular responses induced by arsenic that are attributable to these miRNAs. Data show that arsenic is capable of inducing the expression of many miRNAs, most remarkably, the miRNA-190. In silico analysis of possible miR-190 targets indicated that this miRNA may also be involved in tumor formation by targeting multiple proteins including PHLPP, an AKT phosphatase. Kinase activation analysis demonstrated that miR-190 is able to mediate arsenic-induced AKT activation, and that this may occur in a PHLPP dependant manner. Furthermore, overexpression of a miR-190 precursor can enhance the expression of VEGF, a protein downstream of AKT signaling. These data suggest that arsenic is capable of inducing expression of miRNAs which may play a critical role in arsenic-induced carcinogenesis.
The Toxicologist. Society of Toxicology 49th Annual Meeting and ToxExpo, March 7-11, 2010, Salt Lake City, Utah