Nuclear EGFR Signaling Network in Human Cancer

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发展密切相关，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途径的了解不完整。越来越多的证据揭示了一种新的EGFR信号转导模式，其中EGF配体将EGFR穿梭到细胞核中，导致细胞周期蛋白D1基因激活。与无/低水平EGFR的乳腺肿瘤患者相比，含有高水平EGFR的乳腺肿瘤患者的生存率较差。然而，这种新型EGFR网络的性质和病理学意义在很大程度上仍然未知。我们将测试这一假设，即核EGFR作为转录调节因子和酪氨酸激酶的功能，以及去调节的核EGFR途径有助于人类肿瘤的更具侵略性的生物学。初步数据表明，EGFR和致癌转录因子、信号转导子和转录激活子-3，STATS之间存在一种新的核相互作用，导致诱导型一氧化氮合酶（iNOS）表达增加。目的1研究EGFR/STAT 3在细胞核中的相互作用，并确定其在iNOS基因调控中的作用。此外，核EGFR是否也作为酪氨酸激酶发挥作用仍不清楚。此外，我们还发现EGF可激活上皮间质转化（EMT）/转移的介导因子TWIST的表达，并且TWIST基因启动子可受EGFR、c-jun和STATS的调控。因此，目的2将确定EGFR/ c-jun/STAT 3相互作用对TWIST基因活化和TWIST介导的EMT/肿瘤进展的影响。我们的初步数据表明，细胞核EGFR在紫杉醇/5-Fu耐药中的作用。目的3探讨EGFR介导的细胞核化疗耐药的意义和机制。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。

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.