Role of Dietary Zinc Transporter ZIP4 in Pancreatic Cancer

胰腺癌(PC)是所有癌症中病死率最高的，也是导致癌症的第四大原因。 北美与癌症相关的死亡人数，总体五年存活率不到5%。因此， 迫切需要在PC中识别新的分子靶点，以指导有效药物的选择 治疗。这项提议中的新概念是锌转运蛋白ZIP4调节PC细胞的生长， 肿瘤进展和生存，这表明了ZIP4的一个新的重要作用。我们还发现了 ZIP4在大多数PC标本和PC细胞系中均有不同程度的过表达。强迫性 ZIP4过表达可促进PC细胞增殖和肿瘤生长。相反，ZIP4的沉默由 ShRNA抑制PC生长，提高小鼠存活率，提示ZIP4是一种 潜在的治疗靶点。我们的初步数据也表明microRNA-224(miR-224)是 在ZIP4过表达的细胞和异种移植瘤中表达下调，当ZIP4被沉默时上调。一个 凋亡抑制因子5(API-5)miR-224的潜在靶点在ZIP4的过度表达中上调 ZIP4抑制PC细胞的表达，提示ZIP4介导PC的一种新机制 成长。我们推测ZIP4的异常表达在PC细胞的生长和生长中起关键作用。 肿瘤的进展通过miR-224/API-5途径进行，ZIP4可能是PC的一个新的治疗靶点。 我们建议确定ZIP4a)在K-RAS转基因小鼠模型中的表达是否发生变化 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。我们会 还确定ZIP4的过表达是否下调miR-224的转录，以及b) 通过miR-224/API-5途径影响PC细胞的凋亡。最后，我们将确定a)3个周期 脂质体/ZIP4 shRNA联合治疗；b)脂质体/ZIP4 shRNA联合治疗 吉西他滨对PC小鼠模型有效。这份R01提案中的新发现是 膳食锌转运蛋白ZIP4在大多数PC患者中过表达，并调节PC的生长和 生死存亡。拟议的研究将帮助我们通过以下方式了解ZIP4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.