Role of Dietary Zinc Transporter ZIP4 in Pancreatic Cancer

胰腺癌（PC）是所有癌症中死亡率最高的癌症，也是第四大癌症病因。 在北美，癌症相关的死亡率为50%，总体五年生存率低于5%。因此，我们认为， 迫切需要确定新的分子靶点，以指导有效的治疗方法的选择。 治疗该提案中的新概念是锌转运蛋白ZIP 4调节PC细胞生长， 肿瘤进展和存活，这表明ZIP 4具有新的重要作用。我们还发现 ZIP 4在大多数PC标本和PC细胞系中不同程度地过表达。被迫 ZIP 4的过表达增加PC细胞增殖和肿瘤生长。相反，ZIP 4的沉默， 在小鼠模型中，shRNA抑制PC生长并增加存活率，这表明ZIP 4是一种抑制PC生长的基因。 潜在的治疗靶点。我们的初步数据还表明，microRNA-224（miR-224） 在ZIP 4过表达细胞和异种移植物中下调，并且当ZIP 4沉默时上调。一 发现miR-224的潜在靶点凋亡抑制剂5（API-5）在ZIP 4过表达中上调。 在ZIP 4沉默的PC细胞中表达下调，提示ZIP 4介导PC的新机制 增长我们假设ZIP 4的异常表达在PC细胞生长中起关键作用， 通过miR-224/API-5途径的肿瘤进展，ZIP 4可能是PC的新治疗靶点。 我们提出确定ZIP 4 a）的表达是否在K-Ras转基因小鼠模型中变化， 与肿瘤进展相关，B）与K-Ras转基因小鼠模型中的锌水平相关。我们将 还确定ZIP 4的过表达是否a）下调miR-224的转录，和B） 通过miR-224/API-5途径影响PC细胞凋亡。最后，我们将确定a）3个周期是否 和B）脂质体/ZIP 4 shRNA加 吉西他滨在小鼠模型中对PC有效。R 01提案中的新发现是， 饮食锌转运蛋白ZIP 4在大多数PC患者中过表达，并调节PC生长， 生存拟议的研究将有助于我们了解ZIP 4和PC进展的相关性， 使用分子方法。

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.