Primary Cilia and Malignant Transformation

原发纤毛与恶性转化

• 批准号: 8487699
• 负责人: Sergio A Gradilone
• 金额: $ 17.29万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487699
• 关键词: Architecture; Astrocytoma; Biochemical; Breast; Cell Line; Cells; Chemicals; Cholangiocarcinoma; Cilia; Cilium Microtubule; Computer Simulation; Data; Deacetylase; Deacetylation; Development; Disease; Disease Progression; Down-Regulation; Environment; Epithelial Cells; Erinaceidae; Foundations; Functional disorder; Genes; Glioblastoma; Goals; HDAC6 gene; Hepatocyte; Human; Intervention; Kidney; Knowledge; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; MicroRNAs; Mitogen Activated Protein Kinase 1; Mutation; Neoplastic Cell Transformation; Organelles; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phenotype; Process; Property; Prostate; Regulation; Renal carcinoma; Sensory; Signal Pathway; Signal Transduction; Stimulus; Structure of retinal pigment epithelium; Testing; Therapeutic; Translations; Tubulin; Tumor Suppressor Proteins; Untranslated RNA; Work; anti-cancer therapeutic; base; biliary tract; cell dedifferentiation; cell growth; cholangiocyte; derepression; extracellular; mRNA Transcript Degradation; malignant breast neoplasm; multisensory; neoplastic cell; novel; overexpression; programs; protein expression; public health relevance; research study; restoration; sensor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Our goal is to explore novel tumor suppressor mechanisms dependent on the integrity of primary cilia. Our preliminary data shows the absence of cilia in cholangiocarcinoma cells; therefore, ciliary dysfunction may be associated with cancer development. The mechanisms leading to ciliary reduction in these tumor cells as well as the consequences of such a lost remain unknown. We HYPOTHESIZE that the functional integrity of cholangiocyte primary cilia is required for the transduction of environmental stimuli, and generates intracellular signals that function as tumor suppressors. We propose that in cholangiocarcinoma, (i) decreased microRNAs expression (i.e. mir-433, mir-22, mir-141, mir-200) leads to overexpression of HDAC6, a cytoplasmic deacetylase that induces ciliary resorption, and the subsequent reduction of cholangiocyte primary cilia; and (ii) ciliary loss generates the disengagement between the environment and the cell interior resulting in derepression of tumorigenic factors and cancer development. In Specific Aim #1 we will characterize the effect of ciliary loss on the normal cholangiocyte phenotype. Our working hypothesis, based upon preliminary data, is that primary cilia and the intracellular signals induced by their multisensory functions are constraining Hedgehog and MAPK pathways, which are involved in cancer development. In Specific Aim #2 we will characterize the effect of specific miRNAs downregulated in CCA on cholangiocyte ciliary expression. Our working hypothesis is that the downregulation of mir-433, mir-22, mir-141, and/or mir-200 in CCA induces the overexpression of HDAC6 and the resorption of cilia. Finally, in Specific Aim #3 we will evaluate the effect of cilia restoration on tumor cells. Our working hypothesis is that this intervention isa potential approach for decreasing cell growth and dedifferentiation of cholangiocarcinoma cells. The results of the present proposal will provide novel information regarding the ciliary-dependent mechanisms controlling the proliferation of tumor cells; and will provide the foundation for a plausible anti-cancer therapeutic treatment based on the rescue of primary cilia architecture and function.

描述（由申请人提供）：我们的目标是探索依赖于初级纤毛完整性的新型肿瘤抑制机制。我们的初步数据显示胆管癌细胞中不存在纤毛；因此，纤毛功能障碍可能与癌症的发展有关。导致这些肿瘤细胞纤毛减少的机制以及这种损失的后果仍然未知。我们假设胆管细胞初级纤毛的功能完整性是环境刺激转导所必需的，并产生充当肿瘤抑制因子的细胞内信号。我们提出，在胆管癌中，(i) microRNA 表达（即 mir-433、mir-22、mir-141、mir-200）减少导致 HDAC6 过度表达，HDAC6 是一种细胞质脱乙酰酶，可诱导纤毛吸收，并随后导致胆管细胞初级纤毛减少； (ii)纤毛损失导致环境和细胞内部之间的脱离，从而导致致瘤因子的抑制和癌症的发展。在具体目标#1 中，我们将描述纤毛缺失对正常胆管细胞表型的影响。基于初步数据，我们的工作假设是初级纤毛及其多感觉功能诱导的细胞内信号限制了参与癌症发展的 Hedgehog 和 MAPK 通路。在特定目标#2 中，我们将描述 CCA 中下调的特定 miRNA 对胆管细胞纤毛表达的影响。我们的工作假设是，CCA 中 mir-433、mir-22、mir-141 和/或 mir-200 的下调会诱导 HDAC6 的过度表达和纤毛的吸收。最后，在具体目标#3中，我们将评估纤毛恢复对肿瘤细胞的影响。我们的工作假设是，这种干预是减少胆管癌细胞生长和去分化的潜在方法。本提案的结果将提供有关控制肿瘤细胞增殖的纤毛依赖性机制的新信息；并将为基于挽救初级纤毛结构和功能的合理抗癌治疗奠定基础。