COBRE: UNE MED CTR: P7:MESENCHYMAL TRANSITIONS IN HEAD AND NECK TUMORS

COBRE：UNE MED CTR：P7：头颈肿瘤中的间质转化

• 批准号: 7610588
• 负责人: Ali Nawshad
• 金额: $ 23.24万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610588
• 关键词: Adhesions; Adhesiveness; Affect; Carcinoma; Cell Adhesion; Cell Communication; Cell Maintenance; Cell Polarity; Cell-Cell Adhesion; Cells; Cellular Structures; Computer Retrieval of Information on Scientific Projects Database; Development; Developmental Process; E-Cadherin; Embryonic Development; Epithelial; Epithelium; Fibronectins; Funding; Genes; Grant; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Human; Institution; Invasive; Laboratories; Lymphoid; Malignant Neoplasms; Mesenchymal; Modification; Mus; Pathway interactions; Play; Positioning Attribute; Process; Repression; Research; Research Personnel; Resources; Role; Signal Repression; Signal Transduction; Societies; Source; Structure; Tissues; Transforming Growth Factor beta; United States National Institutes of Health; Vimentin; cancer cell; cell motility; defined contribution; enhancing factor; epithelial to mesenchymal transition; novel; promoter; response; transcription factor; tumor progression; tumorigenesis; Adhesions; Adhesiveness; Affect; Carcinoma; Cell Adhesion; Cell Communication; Cell Maintenance; Cell Polarity; Cell-Cell Adhesion; Cells; Cellular Structures; Computer Retrieval of Information on Scientific Projects Database; Development; Developmental Process; E-Cadherin; Embryonic Development; Epithelial; Epithelium; Fibronectins; Funding; Genes; Grant; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Human; Institution; Invasive; Laboratories; Lymphoid; Malignant Neoplasms; Mesenchymal; Modification; Mus; Pathway interactions; Play; Positioning Attribute; Process; Repression; Research; Research Personnel; Resources; Role; Signal Repression; Signal Transduction; Societies; Source; Structure; Tissues; Transforming Growth Factor beta; United States National Institutes of Health; Vimentin; cancer cell; cell motility; defined contribution; enhancing factor; epithelial to mesenchymal transition; novel; promoter; response; transcription factor; tumor progression; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cell-cell adhesion determines the polarity of cells and participates in the maintenance of the cell societies called tissues. Cell-cell adhesiveness is generally reduced thus allowing cellular migration following an epithelial-to-mesenchymal transition (EMT), a process that occurs in normal developmental processes as well as in human cancers. As a consequence, epithelial cancer cells often lose the morphological hallmarks of typical epithelia as they become invasive and metastatic. Similar modifications of cell-cell interactions are observed duing tumor progression of most carcinomas and has been related to the induction of EMT. We have recently identified a novel pathway where Transforming Growth Factor (TGF)-Beta signals via Smads to activate Lymphoid Enhancing Factor (LEF)-1 to repress E-cadherin expression, thus allowing EMT during mouse embryogenesis. Interestingly, TGF-Beta and Smads have already been implicated during Head and Neck Squamous Cell Carcinoma (HNSCC); however, the mechanisms of activation of downstream signaling and the repression of E-cadherin in response to TGF-beta signaling is largely unknown. Our hypothesis is that TGF-beta signaling represses E-cadherin activity via LEF1 transcription factor resulting in loss of adhesion and thus promoting EMT and invasion in HNSCC. Our laboratory is positioned to make significant contributions to our understanding of E-cadherin function and the role this cellular structure plays in the development of HNSCC. The specific aims are; (1) to determine if TGF-beta represses E-cadherin expression and thereby influences cell adhesion, proliferation and motility in HNSCC. (2) To further study the mechanism of repression of the E-cadherin promoter in response to TGF-beta signaling and activation of the Smad and LEF1 transcription factors during tumorigenesis, and (3) to determine if TGF-beta signaling promotes acquisition of mesenchymal markers such as fibronectin and vimentin in HNSCC. We will use structure/function studies to investigate the mechanism of TGF-beta signaling, the activation of the Smads and LEF1, and investigate the role of this unique pathway in repressing E-cadherin gene activity. Collectively, the studies proposed herein will define the contribution of a novel signaling patway of TGF-beta and its affect on E-cadherin components for cellular motility, invasiveness in HNSCC.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 细胞 - 细胞粘附决定细胞的极性，并参与维持所谓的组织的细胞社会。 细胞 - 细胞粘附性通常会降低，从而允许上皮到间质转变（EMT）后细胞迁移，该过程发生在正常发育过程中以及在人类癌症中。因此，上皮细胞通常会随着典型上皮的形态学标志，因为它们成为侵入性和转移性。 观察到大多数癌的DU肿瘤进展的细胞 - 细胞相互作用类似，并且与EMT的诱导有关。我们最近确定了一种新的途径，其中通过SMADS转换生长因子（TGF）-Beta信号激活淋巴样增强因子（LEF）-1以抑制E-钙粘蛋白的表达，从而在小鼠胚胎发生过程中允许EMT。有趣的是，在头颈鳞状细胞癌（HNSCC）中，TGF-beta和Smads已经与TGF-beta和Smads有关。然而，下游信号传导激活的机制和对TGF-β信号的响应的抑制是未知的。 我们的假设是，TGF-β信号传导通过LEF1转录因子抑制E-钙粘蛋白活性，从而导致粘附丧失，从而促进HNSCC中的EMT和侵袭。 我们的实验室有能力为我们对电子钙粘蛋白功能的理解做出重大贡献，以及该细胞结构在HNSCC发展中的作用。具体目标是； （1）确定TGF-β是否抑制E-钙粘蛋白的表达，从而影响HNSCC中的细胞粘附，增殖和运动。 （2）进一步研究了肿瘤发生过程中对TGF-beta信号传导的抑制机制以及SMAD和LEF1转录因子的激活，以及（3）以确定TGF-BETA信号传导是否促进了Hnsccc中的纤维蛋白和vimentin和vimentin等间质标记的获取。 我们将使用结构/功能研究来研究TGF-β信号传导的机制，SMADS和LEF1的激活，并研究该独特途径在抑制E-钙粘蛋白基因活性中的作用。 总的来说，本文提出的研究将定义TGF-β的新信号通道的贡献及其对E-钙粘蛋白成分的影响，用于细胞运动，HNSCC中的侵入性。