HMGA2：一个潜在预测乳腺癌患者预后的标记物及其分子机理研究

发布时间：2018-04-06 07:10

本文选题：HMGA2　切入点：肿瘤进展　出处：《浙江大学》2017年硕士论文

【摘要】：乳腺癌的发病率在女性恶性肿瘤中居于首位。随着诊断和治疗方式的进步,目前乳腺癌的发病率和死亡率已经逐年降低。手术、化疗、放疗、内分泌治疗、靶向治疗等综合治疗是治疗乳腺癌的新理念。化疗仍是晚期或转移性乳腺癌治疗的主要方式之一。随之而来的化疗耐药是导致肿瘤治疗失败的主要原因之一,超过90%的死亡是由于化疗耐药导致的肿瘤复发或转移[1]。乳腺癌可分为四个主要的分子亚型:LuminalA,LuminalB,HER2阳性型和三阴性乳腺癌(TNBC)。内分泌治疗是Luminal型乳腺癌的主要治疗方式,HER2靶向治疗是那些HER2阳性乳腺癌的有利治疗方式。然而,TNBC往往预后较差并且缺乏常规化疗药物持续应答[2]。目前国内外学者仍然持续不断努力寻找新的有效的可以用来准确预测化疗药物敏感性的标记蛋白。高迁移率族蛋白A2(high mobility group protein A2,HMGA2)属于非组蛋白染色体蛋白,是一种构筑型转录因子,其自身缺乏转录活性,但是含有三个特殊的AT-hook结构,可与DNA上AT序列富集区域结合,改变基因的DNA构象,促进或抑制相关靶基因的表达,从而影响胚胎的形成发育。近年来,HMGA2因其具有广泛的致癌作用被受到关注。HMGA2可以作为一个转录因子调控下游基因的表达,在胚胎发育或者肿瘤发生过程中起到维持细胞的未分化状态的作用[3-5]。HMGA2被视为一种癌胚蛋白,其在胚胎时期高表达而在正常成熟细胞中不表达,但是在恶性肿瘤中又能高表达,如在胰腺癌[6]、脂肪肉瘤[7]、膀胱癌[8]等癌症中都能检测到HMGA2表达且与肿瘤分化程度或者预后相关。HMGA2在结直肠癌中表达增高与肿瘤的远处转移及预后不良显著相关,且HMGA2表达与结直肠癌患者对放疗敏感性相关[9]。有学者报道在乳腺癌组织中HMGA2的mRNA水平表达升高并且与低分化病理类型相关[10]。在乳腺癌患者外周血中也可以检测到HMGA2的mRNA水平升高[11]。但是在乳腺癌中关于HMGA2蛋白水平表达变化与预后的相关研究仍然未见系统的报道。为了进一步了解HMGA2与乳腺癌患者预后之间的关系以及HMGA2与化疗药物敏感性之间的关系,本文第一部分通过检测乳腺癌样本的HMGA2的表达,进行相关生存预后分析。第二部分我们进行相关细胞功能学机制研究,将MCF-7及SKBR-3两种乳腺癌细胞转染过表达HMGA2后进行相关实验研究,探索HMGA2在乳腺癌细胞中所产生的致癌作用以及其对化疗药物阿霉素影响的作用机制。第一部分HMGA2表达与乳腺癌患者预后关系的研究目的:通过临床组织样本检测HMGA2表达,分析HMGA2表达与乳腺癌患者预后的关系,HMGA2是否为乳腺癌患者预后的一个独立预测因素。方法:1.收集乳腺癌样本:在浙江大学医学院附属第二医院及上海生物芯超国家工程中心收集共583例乳腺癌样本,所有样本均通过电话随访获得随访数据资料。2.构建组织芯片3.采用免疫组化染色获得乳腺癌样本HMGA2的表达情况。4.统计学分析:应用SPSS Statistics 19.0软件,数据分析采用spearman相关性分析,logistic回归分析,Kaplan-Meier生存分析,COX回归分析,P0.05时其差异有统计学意义。结果:1.HMGA2在乳腺癌组织中的表达率有50%-65%左右,HMGA2在病理分化程度为G3乳腺癌组织中表达率最高。2.HMGA2表达的乳腺癌患者的预后比不表达HMGA2的乳腺癌的预后明显差,COX回归分析显示HMGA2表达对预后影响的HR为4.24(1.17,15.37)和2.06(1.21,3.49)。结论:1.HMGA2在乳腺癌组织中的表达与肿瘤分化程度相关;2.HMGA2表达与乳腺癌不良预后相关,HMGA2是乳腺癌患者不良预后的独立预测因素。第二部分HMGA2促进乳腺癌细胞迁移与侵袭,HMGA2促进p53(ser15)磷酸化表达导致阿霉素耐药目的:在细胞水平上研究HMGA2的致癌作用,探讨HMGA2影响化疗药物阿霉素作用效果的机制。方法:通过病毒转染乳腺癌细胞获取高表达HMGA2的乳腺癌细胞系。CCK-8试验检测HMGA2对乳腺癌细胞的生长能力的影响,Transwell实验检测HMGA2对乳腺癌细胞迁移与侵袭能力的影响。阿霉素处理乳腺癌细胞后检测HMGA2对阿霉素作用效果的影响。结果:1.HMGA2高表达乳腺癌细胞与HMGA2低表达乳腺癌细胞的增殖能力无差异,但是Transwell实验结果显示HMGA2高表达乳腺癌细胞更容易穿过Matrigel小室,并且HMGA2高表达乳腺癌细胞的E-cadherin蛋白表达明显降低。2.阿霉素处理细胞后,HMGA2高表达乳腺癌细胞的增殖能力比HMGA2低表达乳腺癌细胞明显高;在阿霉素处理24小时后,HMGA2高表达乳腺癌细胞的p53(serl5)表达明显增高。结论:1.HMGA2通过诱导上皮间质转化(EMT)促进乳腺癌细胞迁移与侵袭能力。2.HMGA2促进p53(ser-15)磷酸化表达增加乳腺癌细胞对阿霉素耐药性。
[Abstract]:Breast cancer incidence is the first in women with malignant tumors . With the advancement of diagnosis and treatment , the incidence and mortality rate of breast cancer has been reduced year by year . Chemotherapy , chemotherapy , radiotherapy , endocrine therapy , targeted therapy and other comprehensive treatment are the main methods for the treatment of breast cancer . Chemotherapy is still one of the main causes of advanced or metastatic breast cancer . More than 90 % of the death is due to the tumor recurrence or metastasis caused by chemotherapy resistance . Breast cancer can be divided into four major molecular subtypes : LuminalA , LuminalB , HER2 - positive , and triple - negative breast cancer ( TNBC ) . endocrine therapy is the primary treatment modality for Luminated breast cancer , and HER2 targeting therapy is an advantageous treatment for those HER2 - positive breast cancer . However , TNBC is often poor in prognosis and lacks conventional chemotherapy drugs for persistent response . High mobility group protein ( A2 ) belongs to non - histone chromosomal protein , it is a kind of construct type transcription factor , it is a kind of construct type transcription factor , it lacks transcriptional activity itself , but it has three special AT - hook structure . It can be used as a transcription factor to regulate the expression of downstream gene . It can be used as a transcription factor to regulate the expression of downstream gene . It can be used as a transcription factor to regulate the expression of downstream gene . It was reported that the level of mRNA levels of HMG - A2 in breast cancer tissues was elevated and associated with low - differentiated pathological types . In the peripheral blood of patients with breast cancer , it was also possible to detect an increase in the mRNA level of HMG - A2 . In order to further understand the relationship between the prognosis of breast cancer patients and the relationship between the prognosis of breast cancer patients , the results showed that 1 . The prognosis of breast cancer patients was higher than that in breast cancer patients .

【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R737.9

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