Roles of Zinc Transporter ZIP4 (SLC39A4) in Pancreatic Cancer Pathogenesis

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DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in North America with an overall five-year survival rate of only 5%. Therefore, there is an urgent need to identify molecular targets regulating PC pathogenesis that could guide new effective treatment strategies. Furthermore, the recent mandate to develop personalized genomic medicine suggests that the genomic profile of molecular targets should be studied in patients with PC. The novel finding in this R21 proposal is that the zinc transporter, Zrt-, Irt-like protein-4 (ZIP4), regulates PC cell proliferation and tumor progression and that the regulation occurs via the IL-6/STAT3 pathway. We have also found that ZIP4 is overexpressed in a majority of PC specimens and PC cell lines to varying degrees. Forced overexpression of ZIP4 increased PC cell proliferation and tumor progression. Conversely, silencing of ZIP4 by shRNA inhibited PC growth and increased survival rate of nude mice with PC xenografts, suggesting that ZIP4 is a potential therapeutic target. STAT3 was activated in ZIP4 over-expressing MIA PaCa-2 cells, and IL-6 and cyclin D1 expression were upregulated by ZIP4 overexpression in PC cells and xenografts. We hypothesize that ZIP4 regulates PC proliferation and tumor progression via the IL-6/STAT3 pathway. We propose to determine whether the expression level of ZIP4 a) varies in patients with PC and correlates with stage and survival in 2 cohorts of patients with PC, b) regulates PC cell proliferation and tumor progression in different PC cell lines and a PC mouse model. We will also determine whether overexpression of ZIP4 a) upregulates the transcription of IL-6 through CBP/CREB transcription factors, and b) affects PC cell proliferation and tumor progression via the IL-6/STAT3 pathway. The novel findings in this R21 proposal are that ZIP4 is overexpressed in majority of patients with PC and regulates PC cell proliferation via the IL-6/STAT3 pathway. Novel strategies targeting ZIP4 will be developed and tested in animal models of PC. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer-related deaths in North America, therefore, there is a pressing need for more effective diagnostic and treatment strategies. The novel finding in this proposal is that the zinc transporter protein ZIP4 regulates pancreatic cancer growth, which assigns a new and important role for ZIP4. Our preliminary data support that hypothesis that ZIP4 might be a therapeutic target for pancreatic cancer, and this study will lead to meaningful advances for understanding this horrible disease.