Pancreatic cancer (PC) has the number one fatality rate of all cancers, and is the fourth leading cause of cancer-related deaths in North America, with an overall five-year survival rate less than 5%. Therefore, there is an urgent need to identify novel molecular targets in PC that could guide the choice of effective therapies. The novel concepts in this proposal are that a zinc transporter, ZIP4, regulates PC cell growth, tumor progression, and survival, which suggests a new and important role for ZIP4. We have also found that ZIP4 is overexpressed in majority of PC specimens and PC cell lines to varying degrees. Forced overexpression of ZIP4 increases PC cell proliferation and tumor growth. Conversely, silencing of ZIP4 by shRNA inhibits PC growth and increases the survival rate in a mouse model, suggesting that ZIP4 is a potential therapeutic target. Our preliminary data also demonstrate that microRNA-224 (miR-224) is downregulated in ZIP4 over-expressing cells and xenografts, and is upregulated when ZIP4 is silenced. A potential target of miR-224, apoptosis inhibitor 5 (API-5), is found to be upregulated in ZIP4 overexpressing PC cells and downregulated in ZIP4 silenced PC cells, suggesting a new mechanism of ZIP4-mediated PC growth. We hypothesize that the aberrant expression of ZIP4 plays a critical role in PC cell growth and tumor progression through the miR-224/API-5 pathway, and ZIP4 may be a novel therapeutic target for PC. We propose to determine whether the expression of ZIP4 a) varies in a K-Ras transgenic mouse model and correlates with tumor progression, b) correlates with zinc levels in a K-Ras transgenic mouse model. We will also determine whether overexpression of ZIP4 a) downregulates the transcription of miR-224, and b) affects PC cell apoptosis through the miR-224/API-5 pathway. Finally, we will determine whether a) 3 cycles of liposome/ZIP4 shRNA treatment, and b) combinational therapy of liposome/ZIP4 shRNA plus gemcitabine is effective on PC in a mouse model. The novel findings in this R01 proposal are that the dietary zinc transporter ZIP4 is over-expressed in majority of patients with PC and regulates PC growth and survival. The proposed studies will help us to understand the correlation of ZIP4 and PC progression by using molecular approaches.
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 dietary 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.
|Cui, Xiaobo; Zhang, Yuqing; Yang, Jingxuan et al. (2014) ZIP4 confers resistance to zinc deficiency-induced apoptosis in pancreatic cancer. Cell Cycle 13:1180-6|
|Zhang, Yuqing; Chen, Leon; Yang, Jingxuan et al. (2013) Study human pancreatic cancer in mice: how close are they? Biochim Biophys Acta 1835:110-8|
|Lin, Yi; Chen, Yong; Wang, Yongzhi et al. (2013) ZIP4 is a novel molecular marker for glioma. Neuro Oncol 15:1008-16|
|Chen, Leon; Zhang, Yuqing; Yang, Jingxuan et al. (2013) Vertebrate animal models of glioma: understanding the mechanisms and developing new therapies. Biochim Biophys Acta 1836:158-65|
|Zhang, Yuqing; Yang, Jingxuan; Cui, Xiaobo et al. (2013) A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth. EMBO Mol Med 5:1322-34|
|Yang, J; Zhang, Y; Cui, X et al. (2013) Gene profile identifies zinc transporters differentially expressed in normal human organs and human pancreatic cancer. Curr Mol Med 13:401-9|
|Wang, Y; Zhang, Y; Yang, J et al. (2012) Genomic sequencing of key genes in mouse pancreatic cancer cells. Curr Mol Med 12:331-41|
|Ni, Xiaoling; Long, Jiang; Cen, Putao et al. (2012) Pancreatic cancer tumour initiating cells: the molecular regulation and therapeutic values. J Cell Mol Med 16:988-94|
|Mao, Hua; Lebrun, Drake G; Yang, Jingxuan et al. (2012) Deregulated signaling pathways in glioblastoma multiforme: molecular mechanisms and therapeutic targets. Cancer Invest 30:48-56|
|Long, Jiang; Zhang, Yuqing; Yu, Xianjun et al. (2011) Overcoming drug resistance in pancreatic cancer. Expert Opin Ther Targets 15:817-28|