Nuclear EGFR Signaling Network in Human Cancer

人类癌症中的核 EGFR 信号网络

• 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
• 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

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）与人类癌症的起源和进展至关重要，被认为是抗癌治疗的有吸引力的靶标。但是，抗EGFR疗法的临床成功部分仍然有限，部分原因是我们对EGFR途径的了解不完全。积累的证据揭示了一种新型的EGFR信号传导模式，其中EGF配体将EGFR驶入细胞核，从而导致细胞周期蛋白D1基因激活。与没有/低水平的患者相比，含有高核EGFR的乳腺肿瘤的患者幸存下来。但是，这个新型EGFR网络的性质和病理意义在很大程度上未知。我们将检验以下假设：核EGFR既是转录调节剂又是酪氨酸激酶，并且核EGFR途径取消了核EGFR途径有助于人类肿瘤的更具侵略性的生物学。预先数据表明EGFR和致癌转录因子，信号传感器和转录3的激活因子之间的新核相互作用，导致诱导型一氧化氮合酶（INOS）的表达增加。 AIM 1将表征核EGFR/STAT3相互作用，并确定其在INOS基因调节中的作用。此外，核EGFR是否还充当酪氨酸激酶仍然未知。有趣的是，初步结果表明核EGFR磷酸化C-Jun。此外，我们发现EGF激活了Twist的表达，这是上皮 - 间质转变（EMT）/转移的介体，并且可以通过EGFR，C-JUN和Stats调节扭曲基因启动子。因此，AIM 2将确定EGFR/C-JUN/STAT3相互作用对扭曲基因激活和扭曲介导的EMT/肿瘤进展的影响。我们的初步数据建议核EGFR在紫杉醇/5-FU抗性中的作用。 AIM 3将确定核EGFR介导的化学抗性的显着性和机制。该提案与公共卫生高度相关，其结果将介绍到人类癌症中的核EGFR信号网络中。