摘要
本论文共分为三个部分,本研究的第一部分旨在研究循环肿瘤细胞(CTC)与肺癌TNM分期和肿瘤标志物的相关性。肺癌是严重威胁人类健康的疾病,其病死率居恶性肿瘤之首,发病率呈逐年上升趋势。肺癌患者的5年生存率仅8%～15%。多数患者在病程中出现脑、骨、肾上腺、肝脏等远端器官转移,严重影响患者的预后,而血液循环系统是实体肿瘤远处转移的必要途径之一,血液循环中的肿瘤细胞具有与原发灶内瘤细胞相似的基因遗传学特征,有研究指出肿瘤的复发及远端转移可能与肿瘤切除前CTCs的入血有关,因此CTCs有望成为指导治疗和判断预后的敏感指标。本研究旨在分析肺癌患者CTC水平与TNM分期、肿瘤标志物和肺癌分类的相关性。我们以2010年8月至2010年12月在北京世纪坛医院就诊的42例肺癌患者作为研究对象,采集患者静脉血标本,应用免疫磁珠阴性富集分离及细胞免疫荧光染色的方法,检测静脉血中CK18+/DAPr/CD45-CTC计数,同时检测肿瘤标志物Cyfra21-1.NSE.CA199.CA125.CA153.CEA.AFP,并结合影像学、病理学检查结果进行TNM分期,对CTC和TNM分期、肿瘤标志物之间的相关性进行分析。结果发现T1期患者中,CTC计数以1～2为主(4/8,50%),而在T2～T4期的患者中,CTC计数以≥3为主(6/14,42.86%；5/8,62.5%；6/10,60%)。利用影像学检查发现有转移即分期为M1的肺癌患者中,都可检测出CTC。对于总的TNM分期,Ⅰ期患者的CTC计数以1～2为主(5/10,50%),Ⅱ、Ⅲ、Ⅳ期患者以CTC≥3为主(5/11,45.45%；6/11,54.55%；7/10,70%)。值得注意的是Ⅳ期肺癌患者均可检测出CTC。与Cyfra21-1正常组患者相比,Cyfra21-1升高组的患者其CTC检出阳性率增高(58.52%vs.95.45%,P=0.013)。综上所述,CTC计数与肿瘤大小、侵袭性以及远端转移具有一定的相关性,同时其与肿瘤标志物Cfra21-1具有一定相关性。
第二部分旨在研究红细胞体积分布宽度(RDW)和急性心肌梗塞(AMI)预后的相关性,AMI是临床上常见的疾病之一,也是导致死亡的主要原因,在美国等发达国家,每年可有450,000人死于冠心病。心肌梗塞的预后差,首次发生AMI的男性患者病死率为16%,女性患者病死率为28%。红细胞体积分布宽度(RDW)是测定红细胞体积大小变异的一个参数,为血常规检测指标之一。研究表明RDW与心力衰竭以及急性冠脉综合症等心血管疾病患者的预后具有相关性,但至今没有RDW与AMI患者心功能分级(killip分级)之间的相关性研究,以此为着入点,我们间接分析了RDW与AMI患者预后的相关性。对2006年12月-2009年12月入住协和医院的345例AMI患者进行回顾性分析,根据临床症状和肺部有无啰音、啰音范围和收缩压进行Killip分级,检测患者的RDW、血红蛋白(Hb)、血细胞比容(HCT)、平均红细胞体积(MCV)、BNP以及hs-CRP等指标。分析Killip各级之间RDW的变化趋势,同时对RDW与BNP和hs-CRP之间的相关性进行分析。结果发现,KillipⅡ级及以上患者的RDW值明显高于KillipⅠ级患者的RDW(13.75vs 13.07,P<0.001),但KillipⅡ级、Ⅲ级及Ⅳ级之间RDW值差异无统计学意义(PⅡ/Ⅲ=0.498、PⅡ/Ⅳ=0.418、PⅢ/Ⅳ=0.817), KillipⅠ级患者的RDW值均位于参考范围内。RDW与BNP显著相关(r=0.178,P<0.05),而与hs-CRP不具有相关性(r=0.065,P>0.05)。在校正了年龄、性别、HGB、HCT和MCV等因素后,BNP仍可独立预测RDW(R2=0.032,P<0.05)。综上所述,我们的分析数据表明RDW与AMI患者心功能Killip分级具有一定的相关性,KillipⅠ级患者的RDW值显著低于其他分级患者的RDW值,提示RDW与AMI患者的预后具有一定的相关性。进一步分析发现RDW与BNP显著相关,因此作为一项简单方便、经济快速的检测指标,RDW可作为评估AMI患者预后的新marker。
本研究的第三部分旨在探讨转录因子SALL4在白血病中的表达及其作用机制。有研究表明SALL4与造血发育和血液恶性肿瘤之间具有一定的相关性,本实验室前期研究从分子水平分析了SALL4在急性髓细胞白血病(AML)中的表达情况,比较了急性期AML患者、缓解期AML患者以及健康者的SALL4表达水平,发现急性期AML患者SALL4表达水平(69.01,17.20～120.28)明显高于健康对照组(2.64,1.35～5.41；P<0.01)和缓解期AML患者组(1.14,0.50-1.62；P<0.01)。同时利用RNA干扰技术对急性白血病细胞株THP-1中SALL4基因的表达进行抑制,发现Wnt/β-Catenin信号通路的C-myc、Cyclin D1及β-Catenin基因的表达下调,细胞凋亡率增加。在此基础上,我们利用表达Sall4基因的慢病毒载体感染小鼠造血干细胞后,将其进行异体移植,建立过表达SALL4基因的小鼠模型,通过观察过表达SALL4小鼠是否会发生急性髓系白血病,进一步分析SALL4基因与急性髓系白血病发生发展间的联系。
The thesis contains three parts。In the first part of study, we explore the relation of circulating tumor cells (CTCs) to TNM stage and levels of tumor markers for patients with lung cancer. Lung cancer is the leading cancer of all cancer-related death in most countries. Worldwide,5-year survival rate of lung cancer patient is less than 8 to 15%. Enumeration of CTCs may be valuable for lung cancer treatment and monitoring cancer patient relapse. In the prospective, single-center and small sample study, we tested the levels of CTC in 42 patients with emerging or recurrent lung cancer from Beijing Shijitan Hospital. And some tumor markers such as Cyfra21-1, NSE, CA199, CA125, CA153, CEA and AFP were also measured. The tumor-node-metastasis (TNM) staging was performed based on the results of imageology and pathology. CTC count was 1-2 in 50%(4/8) of patients with T1stage, while the CTC counts of≥3 was majority at the rate of42.86%(6/14),62.5% (5/8) and 60% (6/10) in the patients with T2 to T4 stage respectively. CTC can be detected in all M1 patients. In the patients with TNM stageⅠ, CTC counts of 1-2 was dominated at the rate of 50%(5/10), while the CTC counts of≥3 was primary at the rate of45.45%(5/11),54.5%(6/11) and 70%(7/10) in the patients with TNM stageⅡtoⅣ. It is notable that the patients with TNM stageⅣhad a 100% CTC positive rate (10/10). The CTC positive rate was higher in patients with high level of Cyfra21-1 than those with low Cyfra21-1(95.45%vs.58.52%, P=0.013). In conclusion, CTC is related to the size, invasiveness and the distant metastases of tumor and reflects the activity of tumor cells as well. Additionally CTC is correlated with the level of tumor marker Cyfra21-1.
In the second part of study, we tried to investigate the prognostic role of RDW in Acute myocardial infarction (AMI). AMI remains a leading cause of morbidity and mortality worldwide. It is the leading cause of death in the United States and in most industrialized nations throughout the world. Approximately 450,000 people in the United States die from coronary disease per year. The prognosis of AMI is bad. Red blood cell distribution width (RDW), a numerical measure of the variability in size of circulating erythrocytes, has recently been shown to be a strong predictor of adverse outcomes in patients with heart failure and in patients with acute coronary syndromes, but there was no data about the correlation between RDW and the Killip classification of AMI patients. So we analysed. We performed a post hoc analysis included 345 patients with AMI between December 2006 and December 2009. The Killip classification is executed by cardiologist depended on the clinical symptoms and the tests. RDW, hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), brain natriuretic peptide(BNP) and high-sensitivity C-reactive protein(hs-CRP) were tested to determine the dynamic changes of RDW at different Killip classification of the disease. At the same time, we analyzed the correlation of the level of RDW with the level of BNP and hs-CRP. The RDW of patients in Killip classⅡ、Ⅲand IV was higher than those in Killip class I (13.75 vs 13.07, P＜0.001). But the difference of RDW among Killip Class II, III and IV was not significant(PⅡ/Ⅲ=0.498、PⅡ/IV=0.418、PⅢ/IV=0.817). Plasma BNP (r=0.178, P<0.05) but not hs-CRP (r=0.065, P>0.05) levels correlated with RDW. After adjustment for potential confounders including age, gender, HGB, HCT and MCV, RDW was independently predicted by BNP (r2= 0.032, P< 0.05). In Conclusion RDW value of AMI patients who had heart failure was higher than that of patients who had no evidence of heart failure, so RDW can be used to diagnose the event of heart failure.
In the third part of the study, we discussed the expression and mechanism of SALL4 in acute myeloid leukemia (AML). The forward research of our laboratory show the expression of SALL4 gene in patients with AML, the level of SALL4 expression in patients with AML in acute phase [69.01 (17.20-120.28)] was 26-fold and 61-fold high compared with that in remission phase [2.64(1.35-5.41)] and in healthy control [1.14(0.50-1.62)] (Z=-6.48,-6.83,P<0.01). In addition, we also inhibit the expression level of SALI4 in AML cell line THP-1 and investigate its potential effects on pathogenesis of leukemia. The result show that the inhibition of S ALL4 in leukemia cell line THP-1 downregulates the expression of cell proliferation related genes such as C-myc, Cyclin D1,β-catenin and promoted apoptosis. On the basis of the research, we transfected the SALL4a gene into the HSC of mouse, proceeded heteroplastic transplantation, built animal model that overexpressed SALL4a gene, observed whether the mouse will develop into the AML, and investigated the relation of SALL4 gene to the occurrence and development of AML.
引文
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