儿童急性淋巴细胞白血病SOCS3的表达水平与临床特点、早期治疗反应的相关性

发布时间：2018-06-23 06:18

本文选题：细胞因子信号转导抑制因子-3 + JAK　；参考：《安徽医科大学》2017年硕士论文

【摘要】：目的JAK/STAT信号通路的持续活化在血液系统恶性疾病的发生、发展中发挥着重要的作用。SOCS3(细胞因子信号转导抑制因子3)是JAK/STAT3信号通路最重要的抑制分子之一,并且SOCS3还可以通过调节STAT3的激活影响CD4+CD25+CD127~(low)调节性T细胞(CD4+CD25+CD127~(low)Treg cell)水平,进而抑制机体的抗肿瘤免疫。而通过各种手段上调SOCS-3的表达可以抑制肿瘤细胞的增殖和转移,改善机体的抗肿瘤免疫功能。本研究测定了细胞因子信号转导抑制因子-3(SOCS3)在儿童急性淋巴细胞白血病(ALL)中的表达情况、SOCS3表达水平高低与儿童ALL疾病状态、危险度之间的关系,同时测定了ALL患儿STAT3m RNA表达水平及CD4+CD25+CD127~(low)调节性T细胞水平,探讨SOCS3在儿童ALL疾病状态和危险度评估、肿瘤免疫以及靶向治疗中的应用。方法研究选择了45例确诊ALL的儿童,同时选取了13名健康儿童作为正对照组。患者均来自于2015年01月至2016年01月就诊安徽医科大学第二附属医院儿科血液病区的病人,经过骨髓细胞学、细胞组织化学、白血病免疫分型及MRD筛选,所有病例均符合FAB诊断标准。采用SYBR Green荧光定量PCR的方法检测了45例入组ALL患儿初诊时、诱导缓解期和13例正常儿童骨髓单个核细胞中SOCS3 m RNA和STAT3m RNA表达水平;同时采用免疫荧光组织化学染色联合激光共聚焦显微技术测定ALL患儿骨髓单核细胞中SOCS3的位置与表达量;采用流式细胞术测定了ALL患儿外周血中CD4+CD25+CD127~(low)调节性T细胞水平。分别采用方差分析和秩和检验的方法比较SOCS3 m RNA表达水平与ALL危险度、临床特点的关系。结果1、45例患儿初诊时STAT3m RNA表达水平明显高于正常儿童(P0.05),SOCS3 m RNA的低表达导致STAT3m RNA的表达上调;2、45例患儿初诊时SOCS3 m RNA表达水平明显低于正常儿童(P0.05);诱导缓解期45例患儿的SOCS3 m RNA表达水平与正常儿童无显著差异(P0.05);初诊时中高危组患儿SOCS3m RNA表达水平高于低危组(P0.05);按照中位数法将45例患儿初诊时SOCS3 m RNA表达水平分为高表达组和低表达组,比较2组患儿临床特点发现,SOCS3 m RNA高表达组具有更高的外周血白细胞计数、乳酸脱氢酶水平和预后不良基因。此外,2组在危险度比较时SOCS3 m RNA高表达组危险度更高。3、45例ALL患儿初诊时CD4+CD25+CD127~(low)调节性T细胞(CD4+CD25+CD127~(low)Treg)水平高于正常儿童(P0.05),比较低中高危三组ALL患儿CD4+CD25+CD127~(low)Treg细胞水平,三组之间CD4+CD25+CD127~(low)Treg细胞水平无差异(P0.05)。结论儿童ALL中存在SOCS3的下调,SOCS3的下调会引起STAT3的异常活化;SOCS3 m RNA在初诊时下调而在疾病诱导缓解后恢复正常表达,SOCS3可以作为评价疾病状态的指标;SOCS3 m RNA下调,失去对IL-6/STAT3的负性调节使STAT3 m RNA表达上调,导致白血病细胞持续增殖和CD4+CD25+CD127~(low)Treg细胞水平上调,通过调控SOCS3m RNA表达水平可以调控IL-6/STAT3信号通路和CD4+CD25+CD127~(low)Treg细胞水平,为儿童ALL的肿瘤免疫治疗提供了新的思路。
[Abstract]:Objective the continuous activation of JAK/STAT signaling pathway in the malignant disease of the blood system, plays an important role in the development of.SOCS3 (cytokine signal transduction inhibitor 3) is one of the most important inhibitory molecules of the JAK/STAT3 signaling pathway, and SOCS3 can also regulate the CD4+CD25+CD127~ (low) regulatory T cells by regulating the activation of STAT3. (CD4+CD25+CD127~ (low) Treg cell) level, and then inhibit the body's anti-tumor immunity. The expression of SOCS-3 can inhibit the proliferation and metastasis of tumor cells by various means and improve the immune function of the body. This study determined the cytokine signal transduction inhibitor -3 (SOCS3) in children with acute lymphoblastic leukemia (AL) (AL). L) expression, the relationship between the level of SOCS3 expression and the risk degree of ALL disease in children, the level of STAT3m RNA expression and the regulatory T cell level of CD4+CD25+CD127~ (low) in children with ALL, and the application of SOCS3 in the state and risk assessment of ALL disease in children, the application of tumor immunity and target therapy. 45 children with ALL were selected and 13 healthy children were selected as a positive control group. All patients came from 01 months of 2015 to 01 months in the pediatric hematological area of the Second Affiliated Hospital of Medical University Of Anhui. Through bone marrow cytology, cell histochemistry, leukemia immunization and MRD screening, all cases were in accordance with the FAB diagnosis. SYBR Green fluorescence quantitative PCR was used to detect the SOCS3 m RNA and RNA expression level of SOCS3 m RNA and STAT3m in 13 normal children's bone marrow mononuclear cells at the initial diagnosis of 45 cases of ALL children, and the immunofluorescence histochemical staining combined with laser focal microscopy was used to determine the SOC in the bone marrow mononuclear cells of children with ALL. The position and expression of S3 and the level of CD4+CD25+CD127~ (low) regulatory T cells in peripheral blood of children with ALL were measured by flow cytometry. The relationship between the expression level of SOCS3 m RNA and the ALL risk and clinical characteristics was compared with the method of variance analysis and rank sum test. The expression level of STAT3m RNA in 1,45 cases was significantly higher than that of SOCS3 m RNA. The low expression of Chang Ertong (P0.05), SOCS3 m RNA resulted in the up-regulated expression of STAT3m RNA, and the expression level of SOCS3 m RNA was significantly lower than that of normal children (P0.05) at first diagnosis in 2,45 cases, and there was no significant difference in the expression level between the 45 cases of the induced remission period and the normal children. At risk group (P0.05), the expression level of SOCS3 m RNA was divided into high expression group and low expression group at the initial diagnosis of 45 children. The clinical characteristics of the 2 groups were compared with the high expression of SOCS3 m RNA in the high expression group, the level of lactate dehydrogenase and the ungood prognosis. In addition, the 2 groups were higher in SOCS3 m RNA higher when the risk was compared. CD4+CD25+CD127~ (low) regulatory T cells (CD4+CD25+CD127~ (low) Treg) in children with.3,45 (low) were higher than normal children (P0.05) at first diagnosis in the expression group, and the level of CD4+CD25+CD127~ (low) cells in the lower middle risk group of three groups of ALL was compared with those of the three groups. The downregulation of SOCS3 and the downregulation of SOCS3 may cause abnormal activation of STAT3; SOCS3 m RNA is down down at the first diagnosis and restores normal expression after the remission of disease induction. SOCS3 can be used as an index for evaluating the state of disease; SOCS3 m RNA is down, and the negative regulation of IL-6/STAT3 makes the expression of STAT3 cells up up, leading to the continuous proliferation of leukemic cells. The level of CD4+CD25+CD127~ (low) Treg cells was up-regulated, and the level of IL-6/STAT3 signaling pathway and CD4+CD25+CD127~ (low) Treg cell could be regulated by regulating the expression of SOCS3m RNA, which provided a new idea for the tumor immunotherapy of ALL in children.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R733.71

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