Long-term human exposure to inorganic arsenic induces lung, skin, bladder and liver cancer. The molecular mechanisms of arsenic-induced carcinogenesis remain to be elucidated. Our preliminary studies show that long-term exposure to arsenic induces EGFR via miR-370 suppression, which activates PKM2 and NF-?B; and induces PKM2 expression via downregulation of miR-199a expression and Nrf2 overexpression. HIF-1? is also a direct target of miR-199a. PKM2 interacts with p65 and HIF-1? to activate NF-?B and HIF-1 signaling. We further demonstrated that arsenic-transformed (As-T) lung epithelial cells form tumors in vivo and secrete factors CXCL8 and CXCL5, the downstream effectors of PKM2, to activate angiogenesis. We have established a novel chimeric tumor model to study the crosstalk of signaling molecules in As-T cells and human endothelial cells 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 and upregulation 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 and tumor growth.
Aim 3 will investigate the role and mechanism of PKM2 in mediating interactions of As-T cells and endothelial cells and in regulating tumor angiogenesis. This K02 will help foster the candidate?s ability to achieve these research goals by providing her with protected time to be fully engaged in her career development 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 and mechanisms of Cr(VI)-induced carcinogenesis and whether miRNAs such as miR-143 and cytokines such as IL-6 can be used as biomarkers for early detection and prevention of chronic Cr(VI) exposure-related adverse health effects using population study. This K02 will also allow her to focus on studying new mechanism of arsenic in inducing tumorigenesis through PKM2 signaling pathway. Her career development plan involves intense training in techniques and analysis in metal-related carcinogenesis, which will enhance her knowledge and skills in this area. The K02 will be of critical value to expand the candidate?s research program with the potential to discover novel mechanisms of arsenic carcinogenesis that may pave the way to prevent chronic arsenic exposure-caused carcinogenesis by interrupting the novel signaling pathway.
Long-term human exposure to arsenic is known to induce lung cancer. This proposed study will investigate new mechanism of arsenic in inducing carcinogenesis through dysregulation of proteins and microRNAs. The new findings will be important to develop new therapeutic and preventive strategies for cancer(s).
