Nuclear EGFR Signaling Network in Human Cancer

描述(申请人提供)：表皮生长因子受体(EGFR)在人类癌症的发生和发展中起重要作用，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途径的了解不完全。越来越多的证据揭示了一种新的EGFR信号传递方式，即EGF配体将EGFR穿梭到细胞核中，导致细胞周期蛋白D1基因的激活。与无/低水平乳腺癌患者相比，核内EGFR含量高的乳腺癌患者存活率较低。然而，这种新的EGFR网络的性质和病理意义在很大程度上仍不清楚。我们将测试这一假设，即核EGFR既是转录调节因子，又是酪氨酸激酶，并且去调控的核EGFR途径有助于人类肿瘤的更具侵袭性的生物学。初步数据表明，EGFR与肿瘤转录因子、信号转导和转录激活因子-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研究核内EGFR/STAT3相互作用及其在iNOS基因调控中的作用。此外，核内的EGFR是否也具有酪氨酸激酶的功能尚不清楚。有趣的是，初步结果表明，核EGFR使c-jun磷酸化。此外，我们还发现EGF激活了上皮-间充质转化/转移的介导者twist的表达，并且twist基因的启动子可受EGFR、c-jun和STATS的调节。目的2因此将确定EGFR/c-jun/STAT3相互作用在TWIST基因激活和TWIST介导的EMT/肿瘤进展中的作用。我们的初步数据表明，核EGFR在紫杉醇/5-FU耐药中起作用。目的3将确定EGFR介导的核耐药的意义和机制。这项提议与公众健康高度相关，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.