Role of Dietary Zinc Transporter ZIP4 in Pancreatic Cancer

膳食锌转运蛋白 ZIP4 在胰腺癌中的作用

• 批准号: 7886332
• 负责人: MIN LI
• 金额: $ 31.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2010-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886332
• 关键词: Affect; Apoptosis; Apoptosis Inhibitor; Cancer Cell Growth; Cancer Etiology; Cancer cell line; Carrier Proteins; Cell Proliferation; Cells; Cessation of life; Data; Diagnostic; Dietary Zinc; Disease; Genetic Transcription; Growth; Lead; Liposomes; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Molecular; Molecular Target; North America; Pathway interactions; Patients; Play; Role; Specimen; Survival Rate; Transgenic Mice; Xenograft procedure; Zinc; cancer cell; effective therapy; gemcitabine; mouse model; new therapeutic target; novel; overexpression; public health relevance; small hairpin RNA; therapeutic target; treatment strategy; tumor growth; tumor progression; zinc-binding protein

DESCRIPTION (provided by applicant): 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. 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 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.

描述（由申请人提供）：胰腺癌（PC）是所有癌症中死亡率最高的，是北美癌症相关死亡的第四大原因，总体五年生存率低于5%。因此，迫切需要在PC中识别新的分子靶点，以指导有效治疗的选择。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。ZIP 4的强制过表达增加PC细胞增殖和肿瘤生长。相反，通过shRNA沉默ZIP 4抑制PC生长并增加小鼠模型中的存活率，表明ZIP 4是潜在的治疗靶点。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，当ZIP 4沉默时上调。发现miR-224的潜在靶点凋亡抑制剂5（API-5）在ZIP 4过表达的PC细胞中上调，而在ZIP 4沉默的PC细胞中下调，提示ZIP 4介导的PC生长的新机制。我们推测ZIP 4的异常表达通过miR-224/API-5途径在PC细胞生长和肿瘤进展中起关键作用，并且ZIP 4可能是PC的新治疗靶点。我们提出确定ZIP 4的表达a）是否在K-Ras转基因小鼠模型中变化并与肿瘤进展相关，B）是否与K-Ras转基因小鼠模型中的锌水平相关。我们还将确定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个循环的脂质体/ZIP 4 shRNA治疗和B）脂质体/ZIP 4 shRNA加吉西他滨的组合疗法是否对小鼠模型中的PC有效。这项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生长和存活。这些研究将有助于我们通过分子方法了解ZIP 4与PC进展的相关性。 公共卫生关系：胰腺癌是北美癌症相关死亡的第四大原因，因此，迫切需要更有效的诊断和治疗策略。该提案中的新发现是膳食锌转运蛋白ZIP 4调节胰腺癌生长，这为ZIP 4分配了一个新的重要角色。我们的初步数据支持ZIP 4可能是胰腺癌治疗靶点的假设，这项研究将为理解这种可怕的疾病带来有意义的进展。