LRIG1与人脑胶质瘤化疗敏感性的相关性及机制研究

发布时间：2018-05-30 16:16

本文选题：LRIG1 + 人脑胶质瘤　；参考：《武汉大学》2014年博士论文

【摘要】：研究背景与目的：脑胶质瘤是中枢神经系统最常见原发性恶性肿瘤,其治疗难度大,致残率和致死率高,严重威胁患者的生命健康。随着化疗新药替莫唑胺(Temozolomide,简称TMZ)的出现,化疗在脑胶质瘤治疗中的作用被重新重视,大量研究证实TMZ可以明显提高胶质瘤患者的中位生存期,随着对TMZ研究的深入,肿瘤的耐药问题严重制约了TMZ的临床疗效,尤其是肿瘤的多药耐药性(Multidrug resistance,简称MDR)。多亮氨酸重复区免疫球蛋白样蛋白1(简称LRIG1)是近年来发现的一种多RTK抑制剂,LRIG1在人类各种组织中均有表达,在脑组织尤其是胶质细胞中表达量较高,近年来已有多项研究证实LRIG1可以抑制人脑胶质瘤细胞的增殖,是一个新的抑癌基因；但其与胶质瘤化疗敏感性的关系及其机制仍然未知。本研究的目的在于探讨LRIG1与人脑胶质瘤的化疗敏感性的相关性及其机制。方法：收集我院09年-11年手术切除并经病理科证实的胶质瘤标本98例,将这些标本制作成组织芯片并检测其中LRIG1和BCL-2的表达(第一部分)；通过浓度递增法构建人脑胶质瘤多药耐药细胞株U251/MDR并检测LRIG1和BCL-2的表达变化(第二部分)；分别上调和下调LRIG1的表达,CCK-8法检测细胞多药耐药性的变化以确定LRIG1与人脑胶质瘤化疗敏感性的相关性(第三部分)；下调BCL-2在U251/MDR中的表达后我们检测了其多药耐药性的变化,在此基础上我们又下调了LRIG1的表达,CCK-8法检测其多药耐药性的变化,以此确定LRIG1是否可以调节BCL-2的表达(第四部分)。结果：通过检测我们发现LRIG1在人脑胶质瘤组织标本中表达下调,而BCL-2表达上调；成功构建了人脑胶质瘤多药耐药细胞株U251/MDR,其对替莫唑胺、依托泊苷等化疗药物有耐药性,在U251/MDR中LRIG1的表达下调而BCL-2的表达上调；上调LRIG1的表达后胶质瘤细胞对化疗药物的敏感性增强,下调LRIG1的表达后胶质瘤细胞对化疗药物的敏感性下降；在下调BCL-2的基础上再下调LRIG1的表达,可见下调BCL-2后产生的促进化疗敏感性的作用可被LRIG1所改变。结论：LRIG1可以促进人脑胶质瘤的化疗敏感性,其机制与LRIG1调节BCL-2的表达有关。
[Abstract]:Background & objective: glioma is the most common primary malignant tumor in the central nervous system. With the emergence of the new chemotherapeutic drug temozolomide (TMZ), the role of chemotherapy in the treatment of glioma has been revalued. A large number of studies have confirmed that TMZ can significantly improve the median survival time of glioma patients, and with the further study of TMZ, The drug resistance of tumor seriously restricts the clinical effect of TMZ, especially the multidrug resistance of tumor. Polyleucine repeat immunoglobulin-like protein 1 (LRIG1) is a kind of RTK inhibitor found in recent years. It is expressed in various human tissues, especially in glial cells. In recent years, many studies have confirmed that LRIG1 can inhibit the proliferation of human glioma cells and is a new tumor suppressor gene, but its relationship with the chemosensitivity of glioma and its mechanism are still unknown. The aim of this study was to investigate the relationship between LRIG1 and chemosensitivity of human glioma and its mechanism. Methods: 98 cases of glioma were collected from our hospital from 2009 to 11 years after surgical resection and confirmed by pathology. These specimens were made into tissue microarray and the expression of LRIG1 and BCL-2 were detected (part I); the multidrug resistant human glioma cell line U251/MDR was constructed by concentration increasing method and the expression of LRIG1 and BCL-2 was detected (part two; The expression of LRIG1 was up-regulated and down-regulated. CCK-8 assay was used to determine the correlation between LRIG1 and chemosensitivity in human gliomas (part three: after down-regulating the expression of BCL-2 in U251/MDR, we detected the change of multidrug resistance. On this basis, we down-regulated the expression of LRIG1 by CCK-8 method to determine whether LRIG1 can regulate the expression of BCL-2 (part IV). Results: we found that the expression of LRIG1 was down-regulated and the expression of BCL-2 was up-regulated in human glioma tissue, and the multidrug resistant human glioma cell line U251% MDR was successfully constructed, which was resistant to temozolamide, etoposide and other chemotherapeutic drugs. The expression of LRIG1 was down-regulated and the expression of BCL-2 was upregulated in U251/MDR, the sensitivity of glioma cells to chemotherapeutic drugs was enhanced after the up-regulation of LRIG1 expression, and the sensitivity of glioma cells to chemotherapeutic drugs was decreased after down-regulating the expression of LRIG1. On the basis of down-regulation of BCL-2 and down-regulation of LRIG1 expression, we can see that the effect of down-regulating BCL-2 on chemosensitivity can be changed by LRIG1. Conclusion the chemosensitivity of human glioma was enhanced by LRIG1. The mechanism is related to the regulation of BCL-2 expression by LRIG1.
【学位授予单位】：武汉大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R739.41

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