本文選題：Notch1 + IGF-1�。� 參考：《濟南大學》2017年碩士論文

【摘要】：研究背景隨著醫(yī)療水平的不斷提升,特別是在分子生物學技術(shù)的研究方面,人們對非小細胞肺癌的發(fā)病機制有了更深層次的了解,而在非小細胞肺癌的藥物治療研究上,靶點表皮生長因子受體(epidermal growth factor receptor,EGFR)的發(fā)現(xiàn)具有里程碑意義,尤其是對于那些晚期肺癌患者,靶向治療給他們帶來了福音,同時也使得非小細胞肺癌的藥物治療進入了一個全新時代。EGFR是Erb B受體家族的其中一員,該受體家族共有四種受體,分別稱為EGFR(Erb B-1或HER-1)、Erb B-2(HER-2)、Erb B-3(HER-3)和Erb B-4(HER-4)。EGFR發(fā)生基因突變或表達過度會影響腫瘤細胞的發(fā)生發(fā)展。隨之,EGFR抑制劑便應運而生,它針對EGFR為靶點發(fā)揮治療作用,因此特異性高,而且高效;EGFR抑制劑主要分為兩類:即小分子酪氨酸激酶抑制劑(tyrosine kinases inhibitor,TKI)和單克隆抗體(Mab),前者的藥理機制是切割EGFR胞內(nèi)段的酪氨酸激酶結(jié)構(gòu)域與ATP相連接,使磷酸化失敗,并進一步阻擾了下游信號的激活,主要有兩條:MAPK和PI3K/Akt;后者的藥理作用是使EGFR與相應配體結(jié)合失敗,進而EGFR二聚化受阻,從而切斷該條致癌信號通路。EGFR受體與相應的配體結(jié)合可活化EGFR信號通路,促進腫瘤細胞的增生和正常細胞的轉(zhuǎn)化,抑制細胞程序化凋亡,加快腫瘤組織的血管生成,致使腫瘤細胞浸潤、轉(zhuǎn)移,最終導致腫瘤發(fā)生、發(fā)展。EGFR-TKI可抑制腫瘤浸潤和轉(zhuǎn)移,同時可提高腫瘤組織放射敏感性,治療效果顯著。但臨床上發(fā)現(xiàn),EGFR-TKI治療數(shù)月后即產(chǎn)生耐藥,因此研究其中耐藥機制成為熱點。既往研究表明肺癌的發(fā)生與Notch1信號通路的激活密切相關(guān),而EGFR-TKI耐藥是否也Notch1參與有目前尚無研究明確指出,但研究發(fā)現(xiàn)Notch-1是細胞內(nèi)眾多信號通路的交匯點,因此,EGFR信號通路下游的轉(zhuǎn)導通路中很可能與Notch1也存在交叉作用。國外有研究表明Notch-1的促腫瘤生存的功能是通過激活胰島素樣生長因子-1受體(insulin-like growth factors,IGF-1R)來發(fā)揮作用的,但目前對于兩者的表達相關(guān)性分析較少,本研究致力于此,并探討Notch1在非小細胞肺癌靶向藥物耐藥機制,希望能為EGFR-TKI耐藥機制研究尋找出新的突破點,為靶向藥物治療提供新的思路。目的運用免疫組化法檢測非小細胞肺癌中Notch1與IGF-1表達情況,分析兩者在EGFR野生組、EGFR突變組以及EGFR耐藥組中表達的相關(guān)性及臨床意義,并進一步探討EGFR-TKI耐藥機制,為非小細胞肺癌靶向藥物耐藥研究提供新途徑。方法回顧性分析85例NSCLC患者基本病歷資料,按照EGFR基因狀態(tài)的不同劃分為三組,即野生組、突變組和耐藥組,采用免疫組化SP法分別對38例EGFR野生組、28例EGFR突變組,19例耐藥組進行Notch1、IGF-1的蛋白表達檢測。結(jié)果野生組中非小細胞肺癌Notch1、IGF-1陽性表達率分別為26.34%、21.05%,突變組中非小細胞肺癌Notch1、IGF-1陽性表達率分別為39.29%、32.14%,而耐藥組中非小細胞肺癌Notch1、IGF-1陽性表達率則分別為47.39%、42.11%。Notch1在耐藥組中表達明顯高于野生組和突變組,其差異存在統(tǒng)計學意義,F=42.003(P0.001);IGF-1在耐藥組中的表達明顯高于野生組和突變組,其差異存在統(tǒng)計學意義,F=38.179(P0.001)。隨著非小細胞肺癌病理分級的升高和分化程度降低,Notch-1和IGF-1蛋白在三組中的陽性表達率均增高(P0.05);野生組、突變組、耐藥組各組中Notch1與IGF-1的相關(guān)性分析,結(jié)果顯示野生組與突變組中兩者的表達無相關(guān)性(野生組:r=0.278 P=0.091,突變組:r=0.229 P=0.241),差異無統(tǒng)計學意義;但在耐藥組中Notch1與IGF-1呈正相關(guān)(r=0.685 P=0.001),差異有統(tǒng)計學意義。結(jié)論本研究顯示:EGFR耐藥組中Notch1的表達明顯高于其他兩組且差異存在統(tǒng)計學意義(P0.05);EGFR耐藥組中IGF-1的表達明顯高于其他兩組且差異存在統(tǒng)計學意義(P0.05);EGFR耐藥組Notch1、IGF-1表達具有相關(guān)性,在其他兩組中無相關(guān)性;結(jié)合國內(nèi)外相關(guān)研究推測Notch1導致EGFR-TKI耐藥的原因可能是先激活I(lǐng)GF-1,然后進一步激活EGFR下游的Ras/MAPK和P13K/AKT信號通路來完成的,提示Notch1信號高表達可能為EGFR-TKIs耐藥的重要因素。
[Abstract]:Background with the continuous improvement of medical level, especially in the study of molecular biology, people have a deeper understanding of the pathogenesis of non-small cell lung cancer, and the discovery of epidermal growth factor receptor (EGFR) in the drug therapy of non small cell lung cancer has been found. The milestone, especially for patients with advanced lung cancer, has brought them the gospel, and it also makes the drug treatment of non small cell lung cancer enter a new era of.EGFR is one of the Erb B receptor family. There are four receptors in the family, called EGFR (Erb B-1 or HER-1), Erb B-2 (HER-2), Erb B-3 (HER-3) and Erb B-4 (HER-4).EGFR gene mutation or overexpression may affect the development of tumor cells. Accordingly, EGFR inhibitors have emerged as the times require. It is targeted to EGFR as a target and is highly specific and efficient; EGFR inhibitors are mainly divided into two categories: small molecule tyrosine kinase inhibitors (tyrosine kinases inhib) Itor, TKI) and monoclonal antibodies (Mab). The pharmacological mechanism of the former is to connect the tyrosine kinase domain of the EGFR intracellular segment to ATP, which causes the failure of phosphorylation and further obstruct the activation of the downstream signals, mainly two: MAPK and PI3K/Akt; the latter has a pharmacological effect that causes the failure of EGFR to be combined with the corresponding ligands, and thus EGFR dimerization is hindered, The combination of the.EGFR receptor and the corresponding ligand can activate the EGFR signal pathway, promote the proliferation of tumor cells and the transformation of normal cells, inhibit the programmed apoptosis of the cells, accelerate the angiogenesis of the tumor tissue, cause the tumor cells to infiltrate, transfer, and eventually lead to the tumorigenesis, and the development of.EGFR-TKI can inhibit the tumor. Infiltration and metastasis can also improve the radiosensitivity of tumor tissue, and the therapeutic effect is significant. However, it is found that drug resistance occurs after a few months of EGFR-TKI treatment. Therefore, the mechanism of drug resistance has become a hot spot. Previous studies have shown that the occurrence of lung cancer is related to the activation of Notch1 signaling pathway, and whether the drug resistance of EGFR-TKI is also involved in the presence of Notch1. No research has been made before, but the study found that Notch-1 is the intersection of numerous signaling pathways in the cells. Therefore, the downstream transduction pathway in the EGFR signaling pathway is likely to be intersecting with Notch1. Foreign studies have shown that the function of Notch-1 to promote tumor survival is through the stimulated insulin like growth factor -1 receptor (insulin-like GRO). Wth factors, IGF-1R) to play a role, but at present, there is little correlation analysis of the expression of the two. This study is devoted to this, and explores the mechanism of drug resistance of Notch1 in non-small cell lung cancer, hoping to find new breakthrough points for the study of EGFR-TKI resistance mechanism and to provide new ideas for targeting drug therapy. The expression of Notch1 and IGF-1 in non small cell lung cancer was detected by chemical method. The correlation and clinical significance of both in EGFR wild group, EGFR mutation group and EGFR drug resistance group were analyzed, and the mechanism of EGFR-TKI resistance was further explored to provide a new way for the study of drug resistance in non-small cell lung cancer. Methods 85 cases of NSCLC patients were analyzed retrospectively. The data of the medical records were divided into three groups according to the different EGFR gene state, that is, the wild group, the mutant group and the drug resistance group. The immunohistochemical SP method was used to detect the Notch1 and IGF-1 expression of Notch1 and IGF-1 in 38 cases of EGFR wild group, 28 case of EGFR mutation group and 19 cases of drug-resistant group. The positive expression rate of non small cell lung cancer in the wild group was 26.34, respectively. The positive rates of Notch1 and IGF-1 in non small cell lung cancer in the mutant group were 39.29%, 32.14%, respectively, while the Notch1 and IGF-1 positive rates of non small cell lung cancer in the drug resistant group were 47.39%, and 42.11%.Notch1 was significantly higher in the drug resistant group than in the wild group and the mutant group. The difference was statistically significant, F=42.003 (P0.001), and IGF-1 in drug resistance. The expression in the group was significantly higher than that in the wild group and the mutant group. The difference was statistically significant, F=38.179 (P0.001). The positive expression rate of Notch-1 and IGF-1 protein in the three groups increased with the increase of pathological grade and the degree of differentiation of non small cell lung cancer (P0.05), and the correlation between Notch1 and IGF-1 in the wild group, the mutant group and the drug resistant group. The results showed that there was no correlation between the wild group and the mutant group (wild group: r=0.278 P=0.091, mutation group: r=0.229 P=0.241), and there was no significant difference in the difference between Notch1 and IGF-1 (r=0.685 P=0.001) in the drug resistant group (r=0.685 P=0.001), and the difference was statistically significant. Conclusion this study showed that the expression of Notch1 in the EGFR resistant group was significantly higher than that in the drug resistant group. The difference between the other two groups was statistically significant (P0.05), and the expression of IGF-1 in the EGFR resistant group was significantly higher than that of the other two groups, and the difference was statistically significant (P0.05). The EGFR drug resistance group was Notch1, IGF-1 expression was related, and there was no correlation in the other two groups. IGF-1 is activated first and then further activates the Ras/MAPK and P13K/AKT signaling pathways downstream of the EGFR, suggesting that the high expression of Notch1 signals may be an important factor in the resistance of EGFR-TKIs.

【學位授予單位】：濟南大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R734.2

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