New Mechanism of Arsenic Carcinogenesis

Long-term human exposure to inorganic arsenic induces lung, skin, bladder and liver cancer. The molecularmechanisms of arsenic-induced carcinogenesis remain to be elucidated. Our preliminary studies show thatlong-term exposure to arsenic induces EGFR via miR-370 suppression, which activates PKM2 and NF-?B; andinduces PKM2 expression via downregulation of miR-199a expression and Nrf2 overexpression. HIF-1? is alsoa direct target of miR-199a. PKM2 interacts with p65 and HIF-1? to activate NF-?B and HIF-1 signaling. Wefurther demonstrated that arsenic-transformed (As-T) lung epithelial cells form tumors in vivo and secretefactors CXCL8 and CXCL5, the downstream effectors of PKM2, to activate angiogenesis. We have establisheda novel chimeric tumor model to study the crosstalk of signaling molecules in As-T cells and human endothelialcells in regulating tumor angiogenesis. We hypothesize that arsenic induces PKM2 expression via miR-370/miR-199a suppression and Nrf2 upregulation for inducing cell transformation, tumor growth and angiogenesis.To test this hypothesis, three aims are proposed: Aim 1 will investigate the mechanism of PKM2 activation andupregulation induced by arsenic treatment, and determine the role of PKM2 in oncogenic signaling pathway.Aim 2 will investigate the role and mechanism of PKM2 pathway in arsenic-induced cell transformation andtumor growth. Aim 3 will investigate the role and mechanism of PKM2 in mediating interactions of As-T cellsand endothelial cells and in regulating tumor angiogenesis. This K02 will help foster the candidate?s ability toachieve these research goals by providing her with protected time to be fully engaged in her careerdevelopment to become an excellent independent investigator in the field of Environmental Health Science(EHS). She has obtained American Cancer Society Research Scholar Grant to investigate the role andmechanisms of Cr(VI)-induced carcinogenesis and whether miRNAs such as miR-143 and cytokines such asIL-6 can be used as biomarkers for early detection and prevention of chronic Cr(VI) exposure-related adversehealth effects using population study. This K02 will also allow her to focus on studying new mechanism ofarsenic in inducing tumorigenesis through PKM2 signaling pathway. Her career development plan involvesintense training in techniques and analysis in metal-related carcinogenesis, which will enhance her knowledgeand skills in this area. The K02 will be of critical value to expand the candidate?s research program with thepotential to discover novel mechanisms of arsenic carcinogenesis that may pave the way to prevent chronicarsenic exposure-caused carcinogenesis by interrupting the novel signaling pathway.