2010-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/713008摘要：表皮生長因子接受器(Epidermal growth factor receptor; EGFR)是一個重要細胞膜上的接受器，負責許多細胞生長的調控，包括細胞增殖，侵犯和轉移。在受到生長因子活化後，表皮生長因子受體會被活化，進而激活細胞內訊息傳導路徑，包括PI3K/ Akt和MAPK/Erk，在正常細胞和腫瘤細胞中兩者都發揮著重要的生理作用。鑑於表皮生長因子受體參與了各方面的腫瘤形成和惡化，具有多種生理功能，近幾十年來表皮生長因子受體的成為腫瘤標靶治療研發的主要目標之一。然而，臨床上針對表皮生長因子受體的小分子標靶治療唯一證明有效的是在一些特定的，腫瘤有EGFR突變的非小細胞肺癌患者。為何在其他癌症的療效不顯著，原因不明。表皮生長因子接受器有許多變異型(variant form)，其中第三變異型(variant III)因為可以預測表皮生長因子接受器抑制劑於惡性腦瘤之治療效果，最為大家所熟知。我們最近的研究發現一種新的表皮生長因子接受器P120變異型(P-120 variant)，其為基因2-14表現序列(exon 2-14)之惕除。此P120變異型是具有生物活性的，例如，在腫瘤細胞株研究發現若此表皮生長因子接受器P120變異型過度表現下，細胞生長訊息傳遞途徑(AKT及ERK)會活化。又例如，以定量RT - PCR和Western blot分析不同類型的癌症細胞株發現，其表現量與癌細胞株對表皮生長因子受體抑制劑的反應有關。我們也初步證實部分臨床癌腫瘤檢體中確實有此變異型存在。我們的研究目的是：（1）鑑定此新型表皮生長因子受體P120變異型的審議下游訊息傳導機轉（2）初步檢驗在不同癌細胞株以及不同癌症之臨床檢體中此變異型的表現狀態（3）定量臨床乳癌以及肺癌腫瘤檢體中此變異型以及其相關下游訊息傳導分子之表現量，與臨床病理特點作關聯分析，以了解其潛在的臨床意義。<br> Abstract: EGFR regulates numerous cancer cellular processes, including cell proliferation, progression and metastasis. Upon ligand binding, EGFR is activated by phosphorylation of several tyrosine residues within the intracellular kinase domain. Traditionally activated EGFR relays signals by activating various intracellular signal transduction pathways, including Phosphoinositide-3 kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), both of which play important physiological roles in normal and cancerous cells.Because of its diverse functions in cellular physiology, EGFR becomes a major target of tumor therapy in recent decades. However, clinically, EGFR-targeting therapy is only effective in some specific non-small cell lung cancer patients whose tumors have EGFR mutations within the kinase domain. Given the fact that EGFR is involved in various aspects of tumor formation and progression, it is reasonable to expect that EGFR-related inhibitors should have clinical benefits in other cancers. The reason for the limited response of some cancer cells to EGFR-targeting agents is unclear. Emerging evidences suggest the existence of a new mode of epidermal growth factor receptor (EGFR) signalling pathway in which activated EGFR undergoes nuclear translocalization and subsequently regulates gene expression and potentially mediates other cellular processes. Likely via its ability to upregulate gene expression, nuclear EGFR pathway is associated with major characteristics of more aggressive tumours, increased proliferative potential, and accelerated G1/S cell cycle progression.Recently, we identified a novel EGFR transcript variant with a deletion of exons 2-14. This variant mainly exist in nuclear, and may function as an active transcription factor to upregulate Akt and ERK expression. Quantitative RT-PCR and Western blot analysis revealed that this EGFR variant is expressed in various types of cancer cells and its expression level is associated with the responsiveness to EGFR inhibitors.Our specific aims are: (1) to chareaterize the downstream signaling pathways of novel EGFR transcript variant p120 (2) to characterize the expression profile of EGFR transcript variant p120 in different cancer cells and human carcinoma tissue samples (3) to examine the difference of expression level of EGFR transcript variant p120 and related downstream molecules in breast cancer and no-small cell lung cancer, and correlate with the clinical-pathological characteristics.