烟酰胺N-甲基转移酶在胰腺癌发生与发展中的机制研究及临床预后分析

发布时间：2018-02-25 07:10

  本文关键词： 胰腺癌 慢性胰腺炎 NNMT 临床病理特征 预后　出处：《南京医科大学》2017年博士论文　论文类型：学位论文

【摘要】：目的:慢性胰腺炎是部分胰腺癌患者的诱发病因之一。在病灶存在钙化时,从慢性胰腺炎患者中诊断胰腺癌是非常困难的。本研究将研究烟酰胺N-甲基转移酶(NNMT)在慢性胰腺炎与胰腺癌组织中表达差异;根据NNMT在胰腺癌组织中表达量与癌组织大小,患者年龄,癌症发展阶段,预后程度以及CA19-9表达程度等临床特征进行相关性研究。讨论该分子是否可用于区分慢性胰腺炎与胰腺癌,并对NNMT基因在胰腺癌患者预后判断中的意义进行探讨。方法:本研究运用免疫组化检测NNMT在267例患者标本中的表达差异;NNMT在胰腺癌组织中表达量与癌组织大小,患者年龄,癌症发展阶段,进行相关性研究;对胰腺癌患者进行随访将NNMT表达水平以及其他临床特征与胰腺癌患者OS进行分析,探讨NNMT在胰腺癌患者中的预后价值。选取人胰腺癌细胞株 SW1990、CAPAN1、BXPC3、ASPC1、CAPAN2、PATU8988T,利用 siRNA技术对人胰腺癌细胞系中NNMT表达进行下调,探讨NNMT表达对胰腺癌细胞生长凋亡以及转移的影响。结果:在178例胰腺癌组织中,有99例标本NNMT高表达(55.6%);28例28例慢性胰腺炎标本中,有4例标本NNMT基因高表达(14.8%);61例癌旁组织标本,有16例标本NNMT高表达(21.4%),胰腺癌组织NNMT基因表达率显著高于癌旁组织(21.4%)和慢性胰腺炎组织(14.8%)(p0.001)。60岁以上患者中NNMT高表达率为64.2%,高于60岁以下患者(45.8%)p=0.014;肿瘤直径(cm)大于等于4的NNMT表达率为71.8%,高于肿瘤直径(cm)4以下患者(44.9%)p0.001;TNM分期晚期患者中NNMT高表达率为78.2%,高于TNM分期中早期患者(45.5%)p0.001;肿瘤中低分化水平患者中NNMT高表达率为59.2%和60.3%,高于肿瘤高分化患者(17.6%)p=0.004;CA19-9高表达水平(34U/ml)患者NNMT高表达率为64.4%,高于CA19-9低表达水平(34U/ml)患者(43.2%)p = 0.005。NNMT高表达组(NNMTh)和NNMT低表达组(NNMT1)的患者的中位OS为7.0个月(95%CI:5.275-8.725)和 11.5 个月(95%CI:9.759-13.241)(p = 0.005)。除了 NNMT 表达水平,其他因素影响单变量分析的OS中位值包括年龄(p = 0.011),肿瘤直径(p = 0.027),神经系统受累(= 0.033),TNM分期(p = 0.001),远端转移(p0.001)和肿瘤分化程度(p = 0.021)。经多变量分析,NNMT1(危险比[HR]:0.399;95%CI:0.284-0.560;p0.001),无神经系统受累(HR:0.651;950%CI:0.421-0.947;p = 0.041),TNMⅠ 期或 Ⅱ 期(HR:0.506;95%CI:0.299-0.719;p = 0.015)和高度肿瘤分化(HR：0.592;952%CI:0.319-0.894。p = 0.044)为良性预后因素;NNMTh,神经系统受累,TNM Ⅲ期或Ⅳ期和低分化肿瘤为不良预后。NNMTmRNA表达水平较高的胰腺癌细胞系CAPAN1,选取用于后续实验。经实时定量PCR(RT-PCR)与western bloting(WB)检测发现,siRNA干扰实验组与对照组相比NNMT表达量显著降低;Transwell测定siRNA干扰实验组处理的细胞在细胞活动能力明显减弱;MTT检测siRNA干扰实验组凋亡率显著高于对照组。结论:NNMTh与胰腺癌细胞凋亡显着相关。这些结果表明NNMTh与NNMT1相比倾向于与胰腺癌患者不良的相关临床病理特征。通过NNMT在胰腺癌组织、慢性胰腺炎组织与癌旁组织表达量比较,腺癌组织NNMT高表达率显著高于癌旁组织与慢性胰腺炎组织。在有效验证与合理运用下,NNMT表达可能成为区分慢性胰腺炎与胰腺癌的目标靶分子。NNMTh与年龄较大(p = 0.014),较大肿瘤体积(p0.001),高级TNM分期(p0.001),肿瘤中低分化水平(p = 0.004),和CA19-9高表达水平(p = 0.005)显着相关。这些结果表明NNMTh与NNMT1相比倾向于与胰腺癌患者不良的相关临床病理特征。NNMT高表达可视为不良预后,此类患者可能具有较短的生存期。
[Abstract]:Objective: chronic pancreatitis is induced by the cause of pancreatic cancer. In the presence of calcification lesions, the diagnosis of pancreatic cancer from chronic pancreatitis patients is very difficult. The research of nicotinamide N- methyltransferase (NNMT) at different tables in chronic pancreatitis and pancreatic carcinoma; according to the expression of NNMT and cancer the size, in pancreatic cancer patients with age, stage of cancer, study the correlation of clinical features and prognosis of the degree of expression of CA19-9. To discuss whether the molecule can be used to distinguish between chronic pancreatitis and pancreatic cancer, and the prognostic significance of NNMT gene in patients with pancreatic cancer were discussed. Methods: This study used differential expression of immune NNMT were detected in 267 patients in the sample; the expression of NNMT and tumor size in pancreatic cancer patients with age, stage of cancer development, research related to; In patients with pancreatic cancer were the level and other clinical features of patients with pancreatic cancer and OS expression of NNMT, to investigate the prognostic value of NNMT in patients with pancreatic cancer. The selection of human pancreatic cancer cell lines SW1990, CAPAN1, BXPC3, ASPC1, CAPAN2, PATU8988T, NNMT expression was down on human pancreatic cancer cell lines by using siRNA technology to investigate the expression of NNMT, apoptosis and growth effect of metastasis of pancreatic cancer cells. Results: in 178 cases of pancreatic cancer tissues, 99 cases were high expression of NNMT (55.6%); 28 cases of 28 cases of chronic pancreatitis specimens, 4 cases were NNMT gene high expression (14.8%); 61 cases of paracancerous tissues there are 16 samples, the high expression of NNMT (21.4%), NNMT gene expression in pancreatic cancer tissues was significantly higher than that in the adjacent tissues (21.4%) and chronic pancreatitis (14.8%) (p0.001).60 patients over the age of NNMT high expression rate of 64.2%, higher than that of patients under the age of 60 (45.8%) p=0.014; The tumor diameter (CM) greater than or equal to 4, the expression rate of NNMT was 71.8%, higher than the diameter of the tumor (CM) 4 (44.9%) patients with p0.001; TNM staging in patients with advanced NNMT high expression rate of 78.2%, higher than that in patients with early stage TNM (45.5%) p0.001; tumor differentiation level in patients with NNMT high expression rate is 59.2% and 60.3%, higher than that in patients with tumor differentiation (17.6%) p=0.004; CA19-9 high expression level (34U/ml) in patients with NNMT high expression rate of 64.4%, higher than the low expression level of CA19-9 (34U/ml) (P = 43.2%) patients with 0.005.NNMT high expression group (NNMTh) and NNMT low expression group (NNMT1) in OS patients for 7 months and 11.5 months (95%CI:5.275-8.725) (95%CI:9.759-13.241) (P = 0.005). In addition to the expression level of NNMT, other factors including age value of a single variable analysis in OS (P = 0.011), tumor diameter (P = 0.027), nervous system involvement (P = 0.033), TNM stage (P = 0.001), distal. Shift (p0.001) and the degree of tumor differentiation (P = 0.021). In multivariate analysis, NNMT1 (hazard ratio: 0.399; [HR] 95%CI:0.284-0.560; p0.001), no nervous system involvement (HR:0.651; 950%CI:0.421-0.947; P = 0.041), TNM I or II phase (HR:0.506; 95%CI: 0.299-0.719; P = 0.015) and height tumor differentiation (HR:0.592; 952%CI:0.319-0.894.p = 0.044) for benign prognosis; NNMTh, nervous system involvement, TNM III or IV stage and poorly differentiated tumors for pancreatic cancer cell line CAPAN1 poor prognosis in.NNMTmRNA high expression level, were selected for subsequent experiments. The real-time quantitative PCR (RT-PCR) and Western bloting (WB) detection siRNA interference, experimental group compared with the control group, the expression of NNMT was significantly decreased; Transwell determination of siRNA interference in experimental group treated cells was significantly decreased in cell activity; MTT interference detection experiment group the apoptosis rate of siRNA was significantly higher than the control group. Conclusion: NNMTh and pancreatic cancer cell apoptosis significantly. These results indicate that NNMTh and NNMT1 compared with patients with pancreatic cancer prone to adverse clinical and pathological characters. By NNMT in pancreatic cancer, cancer and chronic pancreatitis tissue expression, adenocarcinoma tissues with high expression of NNMT was significantly higher than that in paracancerous tissues and in chronic pancreatitis tissues. And the rational use of effective verification, the expression of NNMT may be to distinguish between chronic pancreatitis and pancreatic carcinoma target molecule.NNMTh and older (P = 0.014), larger tumor volume (p0.001), advanced TNM stage (p0.001), tumor differentiation level (P = 0.004), and the high expression of CA19-9 level (P = 0.005) significantly correlated. These results indicate that NNMTh and NNMT1 compared with patients with pancreatic cancer prone to adverse clinical and pathological characters of high expression of.NNMT can be regarded as a poor prognosis in these patients may have shorter survival Period.

【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R735.9

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