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(申请人提供)：肿瘤细胞对转化生长因子的生长抑制作用有抵抗力？是否仍能分泌转化生长因子？，通过转化生长因子的旁分泌作用促进肿瘤发生？在肿瘤微环境中。阻断这种分泌的转化生长因子？在失去转化生长因子的晚期肿瘤中？生长抑制信号。我们已经确定了在未转化上皮细胞(UECs)和人结肠癌细胞(HCCC)中介导转化生长因子-1产生的信号通路。不同之处之一是AP-1转录因子(TF)与转化生长因子-1启动子的相关区域发生了转换。在这里，我们将探索这种转铁蛋白转换的机制，包括信号复合体的改变区隔所起的作用。此外，我们还鉴定了新奇的转化生长因子？信号中间体km23，它也是运动蛋白dynein(DLC)的轻链。动力蛋白马达复合体可以运输含有转化生长因子？？的膜小泡(即内体隔膜)。受体(T？R‘s)和转化生长因子？在核转位和信号激活之前，信号成分沿着微管被转移到新的囊泡室。在其他马达亚基中，如km23等DLC指定受体内吞后将附着到马达上进行细胞内运输的货物。因此，km23在维持转化生长因子？的适当定位方面起着关键作用。信号复合体。此外，我们已经证明Km23是UEC和HCCC产生转化生长因子-1所必需的。因此，本文提出的研究还将探讨km23调节转化生长因子-1产生所需的MAPK通路的潜在机制，包括确定hccc和uECs在km23控制特定介导转化生长因子-1产生的信号复合体的空间和时间调控方面的差异。人们将试图阻断晚期结肠癌中的结构性(即，不受转化生长因子调节的)转化生长因子-1的产生，以降低体内和体外的致瘤潜能。这一结果将导致设计新的方法，通过阻断在转化生长因子1产生途径信号的时空调节中重要的特定成分，来抑制转化生长因子耐药肝细胞癌的肿瘤进展。因此，拟议的研究将使用一种新的、多维的方法来研究一种新的成分在控制转化生长因子-1的产生中的作用。研究结果应该揭示HCCC和UEC在信号复合体的改变的区划以及信号成分的不同利用方面的显著差异，从而有助于选择性地阻断晚期人类结肠癌中结构性的转化生长因子-1的产生。 这项提案的目标是减少一种促进结肠癌扩散的生长因子的产生。这一结果应该会导致治疗结肠癌的新方法的开发。