本文關鍵詞： 鼻咽癌 4EGI-1 凋亡 治療　出處：《中南大學》2014年碩士論文　論文類型：學位論文

【摘要】：[目的]鼻咽癌(Nasopharyngeal Carcinoma, NPC)是中國南方地區(qū)最為常見惡性腫瘤之一。目前以放化療為主的治療仍不能有效的阻止鼻咽癌的復發(fā)、轉移。真核細胞翻譯起始因子-4E (Eukaryotic initiation factor4E, eIF4E)為帽狀依賴性翻譯過程中的限速因子,eIF4E/eIF4G復合物的組裝在翻譯起始階段的基因表達調控中起關鍵性作用。這一復合物受真核翻譯起始因子4E結合蛋白(4EBPs)調節(jié),4EBPs與eIF4G競爭性地連結至eIF4E。正常細胞中,非磷酸化狀態(tài)的4EBPs與eIF4E結合,限制eIF4E/eIF4G復合物的組裝,從而抑制帽狀依賴性翻譯,影響腫瘤相關蛋白質的翻譯。小分子化合物4EGI-1能干擾eIF4E/eIF4G的相互作用,有效地增加4EBP1與eIF4E結合,下調eIF4E調控的翻譯起始依賴性腫瘤相關蛋白的表達,抑制腫瘤細胞生長和誘導細胞凋亡。我們前期研究發(fā)現(xiàn)4EGI-1具有增加DR5蛋白表達和下調c-FLIP蛋白表達,增加腫瘤壞死因子相關凋亡誘導配體(Tumor necrosis factor-related apoptosis inducing ligand, TRAIL)誘導肺癌細胞凋亡發(fā)揮抗腫瘤作用的功能。但未見4EGI-1在鼻咽癌中的研究報道�；谏鲜銮捌谘芯拷Y果,我們研究4EGI-1對鼻咽癌細胞增殖活性的影響,探討4EGI-1在鼻咽癌中作用的具體分子機制；分析DR4和DR5蛋白表達與鼻咽癌臨床病理特征的相關性,為鼻咽癌的靶向治療和分子靶標的研究提供科學依據(jù)和理論基礎。[方法](1)不同濃度的4EGI-1處理鼻咽癌細胞,流式細胞學檢測鼻咽癌細胞凋亡率,Western blotting檢測c-PARP、Caspase-8、DR5、 HIF-1α、p-4EBP1和DR4蛋白的表達,平板克隆形成檢測4EGI-1對鼻咽癌細胞的放療增敏效果。(2)免疫組化檢測DR4和DR5在鼻咽癌組織中的蛋白表達水平。[結果](1)4EGI-1誘導鼻咽癌細胞凋亡,顯著抑制鼻咽癌的增殖活性；(2)4EGI-1增加鼻咽癌細胞c-PARP、 Caspase8、DR5和HIF-1α蛋白的表達,降低p-4EBP1和DR4蛋白表達；(3)4EGI-1增加2Gy和4Gy放射劑量治療鼻咽癌細胞的療效,增敏比為1.195；(4)臨床Ⅲ-Ⅳ期鼻咽癌組織中DR5蛋白表達顯著低于臨床Ⅰ-Ⅱ期鼻咽癌。(5)伴有淋巴結轉移的鼻咽癌組織中DR5蛋白陽性表達率低于無淋巴結轉移者,鼻咽癌轉移灶的DR5陽性表達也顯著低于與其匹配的原發(fā)鼻咽癌。(6)多因素回歸分析結果也顯示DR5蛋白表達與鼻咽癌淋巴結轉移狀況顯著相關。[結論]1、4EGI-1誘導鼻咽癌細胞凋亡抑制鼻咽癌細胞的增殖活性；4EGI-1增加放射治療鼻咽癌細胞的療效。2、4EGI-1促進鼻咽癌細胞過表達DR5,c-PARP和Caspase8,通過激活死亡受體通路誘導細胞凋亡發(fā)揮抗腫瘤作用。3、DR5蛋白表達降低促進鼻咽癌淋巴結轉移和鼻咽癌患者的臨床進展；DR5蛋白表達可作為評估鼻咽癌淋巴結轉移和治療的分子標志物。我們的研究結果為類似4EGI-1結構的抗鼻咽癌的靶向藥物研究提供科學依據(jù)和理論基礎。圖18幅,表9個,參考文獻79篇。
[Abstract]:[Objective] nasopharyngeal carcinoma (Nasopharyngeal Carcinoma NPC) is one of the most common malignant tumors in South China. Treatment at present is mainly composed of chemotherapy still can not effectively prevent the recurrence of nasopharyngeal carcinoma and metastasis. Eukaryotic translation initiation factor -4E (Eukaryotic initiation factor4E, eIF4E) is the rate limiting factor of cap dependent translation process eIF4E/eIF4G, assembly of complex gene expression in translation initiation plays a key role in the regulation of this complex by eukaryotic translation initiation factor 4E binding protein (4EBPs) regulation, 4EBPs compete with eIF4G to link to eIF4E. in normal cells, 4EBPs and eIF4E phosphorylation state with limited eIF4E/eIF4G assembly compound, inhibits cap dependent translation, influence of tumor associated protein translation. Small molecule 4EGI-1 can interfere with eIF4E/eIF4G interaction, effectively increase 4E BP1 combined with eIF4E, down-regulation of eIF4E expression regulation of translation initiation dependent tumor related protein, inhibit tumor cell growth and induce cell apoptosis. Our previous study found that 4EGI-1 can increase the expression of DR5 and down-regulation of c-FLIP protein expression, increased tumor necrosis factor related apoptosis inducing ligand (Tumor necrosis factor-related apoptosis inducing ligand, TRAIL) induced apoptosis lung cancer cells play the role of anti-tumor function. But there is no research reports of 4EGI-1 in nasopharyngeal carcinoma. The preliminary study based on the results, we study the effect of 4EGI-1 on nasopharyngeal carcinoma cell proliferation activity, to explore the molecular mechanism of action of 4EGI-1 in nasopharyngeal carcinoma; analysis of DR4 and DR5 protein expression correlated with the clinical pathological features of nasopharyngeal carcinoma, and provide scientific based on the theoretical basis and method for nasopharyngeal carcinoma. Study on the targeted therapy and molecular targets of different] (1) 4EGI-1 treatment of nasopharyngeal carcinoma cell concentration, flow cytometry was used to detect the apoptosis rate of nasopharyngeal carcinoma, Western blotting detection of c-PARP Caspase-8, DR5, HIF-1, alpha, p-4EBP1 expression and DR4 protein, colony formation and detection of 4EGI-1 radiotherapy on nasopharyngeal carcinoma cell sensitization effect. (2) immunohistochemistry to detect the expression of DR4 and DR5 in nasopharyngeal carcinoma the protein level. Results (1) 4EGI-1 induced cell apoptosis, inhibit the proliferation of nasopharyngeal carcinoma; (2) 4EGI-1 increased c-PARP, nasopharyngeal carcinoma cell line Caspase8, the expression of DR5 and HIF-1 protein, decreased p-4EBP1 and DR4 protein expression; (3) 4EGI-1 2Gy and 4Gy increase the efficacy of radiation dose in treatment of nasopharyngeal carcinoma cells. The sensitization enhancement ratio was 1.195; (4) clinical stage III - IV nasopharyngeal carcinoma DR5 protein expression was significantly lower than the clinical stage of nasopharyngeal carcinoma. (5) the positive expression rate of DR5 protein in nasopharyngeal carcinoma with lymph node metastasis. Lower than that without lymph node metastasis, the positive expression of DR5 in nasopharyngeal carcinoma metastasis foci was significantly lower than that of matched primary nasopharyngeal carcinoma (6). Multivariate regression analysis showed that DR5 protein expression was significantly related to metastasis. Conclusion]1,4EGI-1 induced cell apoptosis inhibition of nasopharyngeal carcinoma cell proliferation activity in nasopharyngeal carcinoma and lymph node; increase the efficacy of radiation therapy.2,4EGI-1 nasopharyngeal carcinoma cell 4EGI-1 in nasopharyngeal carcinoma cells promote expression of DR5, c-PARP and Caspase8, the antitumor effect of.3 through activation of the death receptor pathway induced apoptosis, DR5 protein expression decreased to promote clinical progress of nasopharyngeal carcinoma and lymph node metastasis in patients with nasopharyngeal carcinoma; the expression of DR5 protein can be used as molecular lymph node metastasis of nasopharyngeal carcinoma and evaluate the treatment of our marker. The results for the anti nasopharyngeal carcinoma target similar 4EGI-1 structure to provide a scientific basis and theory to study medicine Basis. 18 drawings, 9 tables, 79 references.

【學位授予單位】：中南大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R739.63

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本文編號：1532582