Nuclear EGFR Signaling Network in Human Cancer

描述（由申请人提供）：表皮生长因子受体（EGFR）在人类癌症的发生和发展中起着至关重要的作用，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途径的了解不完整。越来越多的证据揭示了EGFR信号传导的一种新模式，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。含有高核EGFR的乳腺肿瘤患者与没有或低核EGFR的患者相比，生存率较低。然而，这种新型EGFR网络的性质和病理意义在很大程度上仍然未知。我们将检验核EGFR作为转录调节剂和酪氨酸激酶的假设，以及去调节的核EGFR途径有助于人类肿瘤更具侵袭性的生物学。初步数据表明，EGFR与致癌转录因子、信号转导和转录激活因子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）的表达增加。目的1将描述细胞核EGFR/STAT3相互作用，并确定其在iNOS基因调控中的作用。此外，核EGFR是否也作为酪氨酸激酶起作用仍不清楚。有趣的是，初步结果表明核EGFR使c-jun磷酸化。此外，我们发现EGF激活了TWIST的表达，TWIST是上皮-间质转化(EMT)/转移的介质，并且TWIST基因启动子可以被EGFR、c-jun和STATS调节。因此，Aim 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。我们的初步数据提示核EGFR在紫杉醇/5-Fu耐药中的作用。目的3将确定核egfr介导的化学耐药的意义和机制。这一建议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.