The Cholangiocyte Primary Cilium as a Tumor Suppressor Organelle

 描述（由申请方提供）：胆管癌（CCA）是一种具有胆道分化特征的致死性恶性肿瘤，治疗选择有限。因此，该项目的长期目标是了解CCA的发病机制并开发新的治疗方法。目前的总体目标是探讨胆管细胞脱附的重要性，我们最近发现的一个潜在的病理过程，在CCA的发病机制和进展。中心假设是在CCA中，由输出蛋白-5/miRNA/HDAC 6失调引起的原发性纤毛再吸收破坏了保护胆管细胞免于恶性转化的正常的纤毛依赖性肿瘤抑制信号。具体目标#1将通过测试以下假设来表征CCA中纤毛损失的机制：核-细胞质转运蛋白exportin-5的失调导致肿瘤抑制miRNA（例如mir-433和mir-22）的减少，从而诱导HDAC 6蛋白水平的上调和纤毛损失。具体目标#2将通过检验促进正常、纤毛依赖性、肿瘤抑制外部线索脱离的假设来评估纤毛缺失的后果，从而导致持续的MAPK和Hedgehog信号传导、p53下调和细胞生长。最后，在具体目标#3中，我们将评估CCA动物模型中纤毛拯救的结果。我们的工作假设是，通过靶向HDAC 6（shRNAS或miR）或mir 433和mir-22（miR-模拟物）恢复初级纤毛，通过拯救胆管细胞传递纤毛依赖性肿瘤抑制因子外部信号的能力来改善肿瘤进展。该方法是创新的，因为它提出利用由胆管细胞中初级纤毛的感觉功能诱导的信号传导途径作为肿瘤抑制机制。纤毛只是最近才成为深入研究的主题，由于纤毛发生是潜在的可逆性，针对纤毛的研究是重要的。这项研究意义重大，因为必须确定调节疾病发生和进展的细胞网络，以开发更好的治疗方法。本提案的结果将揭示关于控制恶性细胞增殖的基本纤毛依赖性机制的新的和可推广的信息，并为基于恢复初级纤毛完整性的合理的新型抗癌疗法提供基础。

 DESCRIPTION (provided by applicant): Cholangiocarcinoma (CCA) is a lethal malignancy with features of biliary tract differentiation with limited therapeutic options. Thus, the long-ter goals of this program are to understand the pathogenesis of CCA and develop new therapies for its treatment. The current overall objective is to explore the importance of cholangiocyte deciliation, a potential pathologic process recently discovered by us, in the pathogenesis and progression of CCA. The CENTRAL HYPOTHESIS is that in CCA, primary cilia resorption resulting from exportin-5/miRNA/HDAC6 dysregulation disrupts the normal, ciliary dependent, tumor-suppressor signals that protect cholangiocytes from malignant transformation. Specific Aim #1 will characterize the mechanisms of ciliary loss in CCA by testing the hypothesis that the dysregulation of the nuclear-to-cytoplamic transporter, exportin-5, results in a decrease in tumor suppressing miRNAs, such as mir-433 and mir-22, inducing the upregulation of HDAC6 protein levels and ciliary loss. Specific Aim #2 will assess the consequences of ciliary loss by testing th hypothesis that promotes the disengagement of the normal, ciliary-dependent, tumor- suppressor external cues resulting in persistent MAPK and Hedgehog signaling, p53 downregulation, and cell growth. Finally, in Specific Aim #3 we will evaluate the outcomes of cilia rescue in CCA animal models. Our working hypothesis is that the restoration of primary cilia by targeting HDAC6 (shRNAS or pharmacologically), or mir433 and mir-22 (miR-mimetics), ameliorates tumor progression by rescuing the cholangiocyte ability to transmit ciliary dependent tumor suppressor external cues. The approach is innovative because it proposes to utilize the signaling pathways induced by the sensory functions of primary cilia in cholangiocytes as a tumor suppressive mechanism. Cilia have only recently become the subject of intense investigation, and since ciliogenesis is potentially reversible, studies directed at cilia are important. The proposed research is significant because it is imperative to identify the cellular networks regulating disease initiation and progression in order to develop better therapies. The results of the present proposal will uncover novel and generalizable information on fundamental, ciliary-dependent mechanisms controlling the proliferation of malignant cells and provide the foundation for plausible, novel anti-cancer therapies based on the restoration of primary cilia integrity.