Nuclear EGFR Signaling Network in Human Cancer

人类癌症中的核 EGFR 信号网络

基本信息

批准号：
7664400
负责人：
HUI-WEN LO
金额：
$ 15.14万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-25 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7664400
关键词：
Antibodies Binding Binding Sites Biological CCND1 Gene Amplification Cell Nucleus Clinical Data Databases Detection E-Cadherin EGF gene Epidermal Growth Factor Receptor Epithelial Gene Activation Gene Expression Regulation Genes Genetic Transcription Human Human Biology In Vitro JUN gene Knowledge Ligands Light Malignant Neoplasms Mammary Neoplasms Maps Mediating Mediator of activation protein Mesenchymal Metastatic Neoplasm to the Lung Molecular Nature Neoplasm Metastasis Nitric Oxide Pathway Nuclear Oncogene Proteins Oncogenic Outcome Paclitaxel Pathway interactions Patients Phosphorylation Protein Tyrosine Kinase Proto-Oncogene Proteins c-jun Public Health Receptor Signaling Regulation Resistance Role STAT3 gene Stat3 protein Testing Therapeutic Tyrosine Validation cancer therapy human NOS2A protein in vivo malignant breast neoplasm novel promoter receptor function response success tool transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Epidermal growth factor receptor (EGFR) is critically involved in the genesis and progression of human cancers and is considered as an attractive target for anti-cancer therapy. However, clinical success with anti-EGFR therapy remains limited in part due to our incomplete knowledge of the EGFR pathway. Accumulating evidences revealed a novel mode of EGFR signaling in which EGF ligand shuttles EGFR into the nucleus, leading to cyclin D1 gene activation. Patients with breast tumors that contain high nuclear EGFR survived poorly compared to those with no/low levels. However, the nature and pathological significance of this novel EGFR network remain largely unknown. We will test the hypothesis that nuclear EGFR functions as both a transcriptional regulator and a tyrosine kinase and that de-regulated nuclear EGFR pathway contributes to a more aggressive biology of human tumors. Preminary data indicate a novel nuclear interaction between EGFR and the oncogenic transcription factor, signal transducer and activator of transcription-3, STATS, leading to increased expression of inducible nitric oxide synthase (iNOS). Aim 1 will characterize nuclear EGFR/STAT3 interaction and determine its role in iNOS gene regulation. Moreover, whether nuclear EGFR also functions as a tyrosine kinase remains unknown. Interestingly, preliminary results suggest that nuclear EGFR phosphorylates c-jun. In addition, we found that EGF activates expression of TWIST, a mediator for epithelial-mesenchymal transition (EMT)/metastasis and that TWIST gene promoter can be regulated by EGFR, c-jun and STATS. Aim 2 will thus determine the effect of EGFR/ c-jun/STAT3 interplay on TWIST gene activation and TWIST-mediated EMT/tumor progression. A role of nuclear EGFR in Taxol/5-Fu resistance is suggested by our preliminary data. Aim 3 will determine the significance and mechanisms for nuclear EGFR-mediated chemoresistance. This proposal is highly relevant to public health and its outcome will shed light into the nuclear EGFR signaling network in human cancers.

描述（由申请人提供）：表皮生长因子受体（EGFR）与人类癌症的发生和进展密切相关，被认为是抗癌治疗的一个有吸引力的靶点。然而，抗 EGFR 治疗的临床成功仍然有限，部分原因是我们对 EGFR 通路的了解不完整。越来越多的证据揭示了一种新的 EGFR 信号传导模式，其中 EGF 配体将 EGFR 运送到细胞核中，导致细胞周期蛋白 D1 基因激活。与没有/低水平的患者相比，含有高核 EGFR 的乳腺肿瘤患者的生存率较差。然而，这种新型 EGFR 网络的性质和病理意义仍然很大程度上未知。我们将检验这样的假设：核 EGFR 既充当转录调节因子又充当酪氨酸激酶，并且解除调控的核 EGFR 通路有助于人类肿瘤更具侵袭性。初步数据表明 EGFR 与致癌转录因子、信号转导器和转录 3 激活剂 STATS 之间存在新型核相互作用，导致诱导型一氧化氮合酶 (iNOS) 表达增加。目标 1 将表征核 EGFR/STAT3 相互作用并确定其在 iNOS 基因调控中的作用。此外，核 EGFR 是否也具有酪氨酸激酶的功能仍不清楚。有趣的是，初步结果表明核 EGFR 磷酸化 c-jun。此外，我们发现EGF激活TWIST的表达，TWIST是上皮间质转化（EMT）/转移的介质，并且TWIST基因启动子可以受到EGFR、c-jun和STATS的调节。因此，目标 2 将确定 EGFR/c-jun/STAT3 相互作用对 TWIST 基因激活和 TWIST 介导的 EMT/肿瘤进展的影响。我们的初步数据表明核 EGFR 在紫杉醇/5-Fu 耐药性中的作用。目标 3 将确定核 EGFR 介导的化学耐药性的意义和机制。该提案与公共卫生高度相关，其结果将揭示人类癌症中的核 EGFR 信号网络。