糖皮质激素对ALL细胞Bim、Puma表达的影响及HA14-1诱导ALL细胞凋亡的途径

发布时间：2018-07-10 17:16

本文选题：糖皮质激素 + 细胞凋亡　；参考：《中国医科大学》2006年博士论文

【摘要】：前言急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)是儿童肿瘤中的常见病,随着联合化疗药物的应用,白血病的治愈率在不断提高,但仍有20%病人因临床耐药而复发。糖皮质激素(glucocorticoid,GC)如地塞米松等能有效诱导凋亡,尤其对淋巴细胞影响巨大,已成为治疗白血病的重要抗肿瘤药。目前GC诱导细胞凋亡的机理及耐药机制仍不完全清楚,多数研究认为GC与其受体结合后激活细胞核内的相关基因,通过转录激活或转录抑制基因的表达来调节细胞凋亡。GC耐药机制异常复杂,GC作用通路的任何环节异常均可导致耐药发生,包括GC代谢酶异常、GC受体基因表达异常、GC受体相关蛋白异常、GC作用的靶基因异常,以及能干扰GC反应的其他信号途径的参与等。在GC诱导凋亡及其耐药机制的研究中,Bcl-2家族因具有调节凋亡作用而备受关注。Bcl-2家族分为抗凋亡及促凋亡成员,抗凋亡成员包括Bcl-2、Bcl-xL等,促凋亡成员包括Bax、Bak、Bid、Bad、Bim、Puma、Noxa等,其中Bim、Puma等仅含BH3区的BH3-only促凋亡成员成为Bcl-2家族的研究热点。微阵列分析发现,淋巴细胞中GC能诱导促凋亡蛋白Bim的表达。有报道GC作用于Bim或Puma基因敲除的小鼠后,不能诱导小鼠体内淋巴细胞凋亡,说明Bim及Puma是体内GC诱导淋巴细胞凋亡的重要启动因子。研究发现Bcl-2家族BH3区模拟物HA14-1能诱导细胞凋亡,并能增强肿瘤细胞对化疗药的敏感性。Bcl-2家族成员Bim及Puma在细胞凋亡过程中发挥重要作用,但在GC诱导的白血病细胞凋亡中所起的作用尚不完全清楚,且目前的研究仅限于动物的体内实验及有限的细胞系,与临床的关联不紧密。对Bcl-2家族模拟物HA14-1在GC耐药ALL细胞中的作用及诱导ALL细胞凋亡的途径,目前的研究仍然有限。
[Abstract]:Acute lymphoblastic leukemia (acute lymphoblastic leukemiaall) is a common disease in children's tumors. With the application of combined chemotherapeutic drugs, the cure rate of acute lymphoblastic leukemia is increasing. However, there are still 20% of patients relapse due to clinical drug resistance. Glucocorticoids (GC), such as dexamethasone (Dexamethasone), can induce apoptosis effectively, especially on lymphocytes, which has become an important antitumor drug in the treatment of leukemia. At present, the mechanism of cell apoptosis induced by GC and the mechanism of drug resistance are not completely clear. Most studies suggest that GC binds to its receptor and activates genes related to the nucleus. Regulation of apoptosis by transcriptional activation or expression of transcription suppressor gene; abnormal mechanism of GC resistance; abnormal interaction of GC with any link of the pathway can lead to drug resistance. These include the abnormal expression of GC receptor gene and the target gene abnormality of GC receptor related protein, as well as the involvement of other signal pathways that interfere with GC response. In the study of the mechanism of apoptosis induced by GC and its drug resistance, the Bcl-2 family has attracted much attention for its role in regulating apoptosis. The Bcl-2 family is divided into anti-apoptotic and pro-apoptotic members, including Bcl-2C Bcl-xL, and Bax-BakBidadine BadBadBima PumaAN Noxa and so on, and the anti-apoptotic members include Bcl-2Bcl-xL and so on. BH3-only apoptosis-promoting members such as BH3-only Puma have become the research focus of Bcl-2 family. Microarray analysis showed that GC could induce the expression of apoptotic protein Bim in lymphocytes. It has been reported that GC can not induce apoptosis of lymphocytes in mice after bim or Puma gene knockout, indicating that Bim and Puma are important promoters of GC induced apoptosis of lymphocytes in vivo. It was found that HA14-1, a BH3 mimic of Bcl-2 family, could induce apoptosis and enhance the sensitivity of tumor cells to chemotherapeutic agents. Bcl 2 family members Bim and Puma played an important role in the process of apoptosis. However, the role of GC- induced apoptosis in leukemic cells is not fully understood, and the current research is limited to animal experiments and limited cell lines, and is not closely related to clinical practice. The role of Bcl-2 family mimic HA14-1 in GC resistant all cells and the pathway of inducing apoptosis of all cells are still limited.
【学位授予单位】：中国医科大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：D919

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