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（申请人提供）：对TGF抑制生长的肿瘤细胞？还能分泌TGF吗？通过TGF?的旁分泌作用促进肿瘤发生在肿瘤微环境中。阻断这种分泌的TGF？晚期肿瘤中TGF？生长抑制信号。我们已经确定了介导TGF？1在未转化上皮细胞（UECs）和人结肠癌细胞（HCCCs）中产生。其中一个差异涉及到结合在TGF？1启动子。在这里，我们将探讨这种TF转换的机制，包括信号复合物区隔化改变所起的作用。此外，我们还发现了新的TGF？信号传导中间体km23，也是马达蛋白动力蛋白（DLC）的轻链。动力蛋白运动复合体可以运输含有TGF？受体(T ?R's)和TGF？在核易位和信号激活之前，信号成分沿着微管到达一个新的囊泡室。在其他运动亚基中，dlc如km23指定在受体内吞作用后附着在运动上进行细胞内运输的货物。因此，km23在维持TGF？信号复合物。另外，我们已经证明了TGF？uec和hccc的生产均为1。因此，本文提出的研究也将探讨km23调节TGF？1的产生，包括鉴别HCCCs和UECs在km23对特异性介导TGF？1生产。会尝试阻断本构(即TGF？-调节)TGF？1 .用于晚期结肠癌，降低体内和体外的致瘤潜能。这些结果应该会导致设计新的方法来抑制TGF？-耐药HCC，通过阻断TGF？1 .生产通路信号。因此，本研究将探讨一种新成分在控制TGF？1生产使用新颖的，多维的方法。研究结果应该揭示HCCC和UEC在信号复合物区隔化改变以及信号成分利用差异方面的显著差异，从而有助于选择性阻断构成型TGF？1在晚期人类结肠癌中的产生。