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: 7472603
• 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/7472603
• 关键词: Abbreviations; Appendix; 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; Primary carcinoma of the liver cells; Production; Proteins; Refractory; Regulation; Relative (related person); Research; Resistance; Role; Role playing therapy; 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; 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）： 肿瘤细胞对 TGF 的生长抑制作用具有抵抗力？仍能分泌TGF?，通过TGF?的旁分泌作用增强肿瘤发生？在肿瘤微环境中。阻断这种分泌的TGF是否有利？在已经失去 TGF 的晚期肿瘤中？生长抑制信号。我们已经确定了在未转化的上皮细胞 (UEC) 和人结肠癌细胞 (HCCC) 中介导 TGF?1 产生的信号通路。差异之一涉及与​​ TGF?1 启动子相关区域结合的 AP-1 转录因子 (TF) 的转换。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，我们还鉴定出了新型TGF？信号中间体 km23，也是运动蛋白动力蛋白 (DLC) 的轻链。动力蛋白运动复合体可以运输含有TGFβ的膜囊泡（即内体区室）？受体（T？R）和TGF？在核易位和信号激活之前，信号成分沿着微管到达新的囊泡区室。在其他运动亚基中，诸如 km23 之类的 DLC 指定了在受体内吞作用后将附着到运动上以进行细胞内运输的货物。因此，km23 在维持 TGF? 的适当定位方面发挥着关键作用。信号复合物。此外，我们还表明，在 UEC 和 HCCC 中，km23 是 TGF?1 产生所必需的。因此，本文提出的研究还将调查 km23 调节 TGF?1 产生所需的 MAPK 途径能力的机制，包括识别 HCCC 和 UEC 在 km23 控制专门介导 TGF?1 产生的信号复合物的空间和时间调节方面的差异。将尝试阻断晚期结肠癌中TGFβ1的组成型（即非TGFβ调节的）产生，以降低体外和体内的致瘤潜力。这些结果应该导致设计新方法，通过阻断在 TGFβ1 产生途径信号传导的空间和时间调节中重要的特定成分来抑制 TGFβ 耐药性 HCC 的肿瘤进展。因此，拟议的研究将使用一种新颖的多维方法来研究一种新成分在控制 TGF?1 产生中的作用。研究结果应揭示 HCCC 和 UEC 在信号复合物区室化的改变以及信号成分的差异利用方面的显着差异，从而有助于选择性阻断晚期人类结肠癌中组成型 TGF?1 的产生。 该提案的目标是减少促进结肠癌扩散的生长因子的产生。这些结果应该会导致治疗结肠癌的新方法的开发。