Mechanisms of TGF-Beta Production in Human Cancer Cells

人类癌细胞中 TGF-β 产生的机制

• 批准号: 7841799
• 负责人: Kathleen M Mulder
• 金额: $ 31.01万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7841799
• 关键词: Abbreviations; Area; Attenuated; Binding; Cells; Colon Carcinoma; Combined Modality Therapy; Complex; Development; Diagnostic Neoplasm Staging; Dynein ATPase; Endocytosis; Endothelial Cells; Epithelial Cells; Event; FOS gene; Fibroblasts; Figs - dietary; Goals; Growth; Growth Factor; Human; Immune; In Vitro; Intracellular Transport; Lead; Ligands; Light; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Microtubules; Mitogen-Activated Protein Kinases; Motor; Movement; Nature; Nuclear Translocation; Oncogenic; Pathway interactions; Peptides; Phosphorylation; Play; Production; Proteins; Refractory; Regulation; Relative (related person); Research; Resistance; Role; Signal Pathway; Signal Transduction; Site; Specific qualifier value; Staging; TGFB1 gene; Testing; Time; Transcription Factor AP-1; Transforming Growth Factor beta; Transmembrane Transport; Tumor stage; Vesicle; acronyms; autocrine; cancer cell; cancer therapy; design; dynein light chain; human RIPK1 protein; in vivo; inhibitor/antagonist; innovation; neoplastic cell; novel; novel strategies; paracrine; promoter; receptor; response; small molecule; trafficking; transcription factor; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Tumor cells that are resistant to the growth inhibitory effects of TGF? can still secrete TGF?, which enhances tumorigenesis via the paracrine effects of TGF? in the tumor microenvironment. It is advantageous to block this secreted TGF? in late-stage tumors that have lost the TGF? growth inhibitory signals. We have identified the signaling pathways mediating TGF?1 production in untransformed epithelial cells (UECs) and in human colon cancer cells (HCCCs). One of the differences involves a switching of the AP-1 transcription factors (TFs) bound to the relevant region of the TGF?1 promoter. Here we will explore the mechanisms underlying this TF switching, including the role played by altered compartmentalization of signaling complexes. In addition, we have identified the novel TGF? signaling intermediate km23, which is also a light chain of the motor protein dynein (DLC). The dynein motor complex can transport membrane vesicles (ie, endosomal compartments) containing TGF? receptors (T?R's) and TGF? signaling components along the microtubules to a new vesicular compartment, prior to nuclear translocation and signal activation. Among other motor subunits, DLCs such as km23 specify the cargo that will be attached to the motor for intracellular transport after receptor endocytosis. Thus, km23 plays a key role in maintaining the appropriate localization of TGF? signaling complexes. In addition, we have shown that km23 is required for TGF?1 production in both UECs and HCCCs. Accordingly, the studies proposed herein will also investigate the mechanisms underlying the ability of km23 to regulate the MAPK pathways required for TGF?1 production, including identifying differences between HCCCs and UECs in km23 control of the spatial and temporal regulation of the signaling complexes specifically mediating TGF?1 production. Attempts will be made to block the constitutive (ie, not TGF?-regulated) production of TGF?1 in advanced-stage colon cancer, to decrease the tumorigenic potential both in vitro and in vivo. The results should lead to the design of novel approaches to suppress tumor progression in TGF?-resistant HCC, via blockade of specific components important in the spatial and temporal regulation of TGF?1 production pathway signaling. Thus, the proposed studies will investigate the role of a novel component in controlling TGF?1 production using a novel, multidimensional approach. The results of the studies should reveal significant differences between HCCC's and UEC's in the altered compartmentalization of signaling complexes, as well as in the differential utilization of signaling components, thereby facilitating efforts to selectively block constitutive TGF?1 production in late-stage human colon carcinomas. The goal of this proposal is to reduce production of a growth factor that enhances the spread of colon cancer. The results should lead to the development of novel approaches to treat colon cancer.

描述（由申请人提供）：对TGF？仍然可以分泌TGF？，通过TGF的旁分泌作用增强肿瘤发生？在肿瘤微环境中。这是有利的，以阻止这种分泌的TGF？在晚期肿瘤中失去TGF？生长抑制信号。我们已经确定了信号通路介导的TGF？1在未转化的上皮细胞（UEC）和人结肠癌细胞（HCC）中的产生。其中一个差异涉及的AP-1转录因子（TF）结合到TGF？1启动子。在这里，我们将探讨这种TF转换的机制，包括改变信号复合物的区室化所发挥的作用。此外，我们已经确定了新的TGF？信号传导中间体km 23，其也是动力蛋白（DLC）的轻链。动力蛋白运动复合物可以运输膜囊泡（即内体室）含有TGF？受体（T？R）和TGF？在核转位和信号激活之前，信号成分沿着微管进入新的囊泡隔室。在其他马达亚基中，DLC如km 23指定将在受体内吞作用后附着于马达用于细胞内转运的货物。因此，km 23发挥了关键作用，在保持适当的本地化TGF？信号复合物此外，我们已经表明，km 23所需的TGF？1在未成年人和高收入国家中的生产。因此，本文提出的研究还将调查潜在的机制，km 23的能力，以调节MAPK途径所需的TGF？1生产，包括确定HCC和UEC之间的差异，在KM 23控制的空间和时间调节的信号复合物特异性介导的TGF？1生产。将尝试阻断组成型（即，不是TGF？-β）调节）生产的TGF？1在晚期结肠癌中，以降低体外和体内的致瘤潜力。这些结果将导致设计新的方法来抑制TGF？耐药HCC，通过阻断在TGF？1生产途径信号。因此，拟议的研究将调查的作用，一个新的组成部分，在控制TGF？1生产使用一种新颖的，多维的方法。研究的结果应该揭示HCCC的和UEC的信号复合物的改变区室化之间的显着差异，以及在信号成分的差异利用，从而促进努力选择性地阻止组成性TGF？1在晚期人类结肠癌中的产生。 这项提案的目的是减少一种促进结肠癌扩散的生长因子的产生。研究结果将有助于开发治疗结肠癌的新方法。