本文關(guān)鍵詞： 胰腺癌 慢性胰腺炎 NNMT 臨床病理特征 預(yù)后　出處：《南京醫(yī)科大學(xué)》2017年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：目的:慢性胰腺炎是部分胰腺癌患者的誘發(fā)病因之一。在病灶存在鈣化時(shí),從慢性胰腺炎患者中診斷胰腺癌是非常困難的。本研究將研究煙酰胺N-甲基轉(zhuǎn)移酶(NNMT)在慢性胰腺炎與胰腺癌組織中表達(dá)差異;根據(jù)NNMT在胰腺癌組織中表達(dá)量與癌組織大小,患者年齡,癌癥發(fā)展階段,預(yù)后程度以及CA19-9表達(dá)程度等臨床特征進(jìn)行相關(guān)性研究。討論該分子是否可用于區(qū)分慢性胰腺炎與胰腺癌,并對(duì)NNMT基因在胰腺癌患者預(yù)后判斷中的意義進(jìn)行探討。方法:本研究運(yùn)用免疫組化檢測(cè)NNMT在267例患者標(biāo)本中的表達(dá)差異;NNMT在胰腺癌組織中表達(dá)量與癌組織大小,患者年齡,癌癥發(fā)展階段,進(jìn)行相關(guān)性研究;對(duì)胰腺癌患者進(jìn)行隨訪將NNMT表達(dá)水平以及其他臨床特征與胰腺癌患者OS進(jìn)行分析,探討NNMT在胰腺癌患者中的預(yù)后價(jià)值。選取人胰腺癌細(xì)胞株 SW1990、CAPAN1、BXPC3、ASPC1、CAPAN2、PATU8988T,利用 siRNA技術(shù)對(duì)人胰腺癌細(xì)胞系中NNMT表達(dá)進(jìn)行下調(diào),探討NNMT表達(dá)對(duì)胰腺癌細(xì)胞生長(zhǎng)凋亡以及轉(zhuǎn)移的影響。結(jié)果:在178例胰腺癌組織中,有99例標(biāo)本NNMT高表達(dá)(55.6%);28例28例慢性胰腺炎標(biāo)本中,有4例標(biāo)本NNMT基因高表達(dá)(14.8%);61例癌旁組織標(biāo)本,有16例標(biāo)本NNMT高表達(dá)(21.4%),胰腺癌組織NNMT基因表達(dá)率顯著高于癌旁組織(21.4%)和慢性胰腺炎組織(14.8%)(p0.001)。60歲以上患者中NNMT高表達(dá)率為64.2%,高于60歲以下患者(45.8%)p=0.014;腫瘤直徑(cm)大于等于4的NNMT表達(dá)率為71.8%,高于腫瘤直徑(cm)4以下患者(44.9%)p0.001;TNM分期晚期患者中NNMT高表達(dá)率為78.2%,高于TNM分期中早期患者(45.5%)p0.001;腫瘤中低分化水平患者中NNMT高表達(dá)率為59.2%和60.3%,高于腫瘤高分化患者(17.6%)p=0.004;CA19-9高表達(dá)水平(34U/ml)患者NNMT高表達(dá)率為64.4%,高于CA19-9低表達(dá)水平(34U/ml)患者(43.2%)p = 0.005。NNMT高表達(dá)組(NNMTh)和NNMT低表達(dá)組(NNMT1)的患者的中位OS為7.0個(gè)月(95%CI:5.275-8.725)和 11.5 個(gè)月(95%CI:9.759-13.241)(p = 0.005)。除了 NNMT 表達(dá)水平,其他因素影響單變量分析的OS中位值包括年齡(p = 0.011),腫瘤直徑(p = 0.027),神經(jīng)系統(tǒng)受累(= 0.033),TNM分期(p = 0.001),遠(yuǎn)端轉(zhuǎn)移(p0.001)和腫瘤分化程度(p = 0.021)。經(jīng)多變量分析,NNMT1(危險(xiǎn)比[HR]:0.399;95%CI:0.284-0.560;p0.001),無(wú)神經(jīng)系統(tǒng)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)和高度腫瘤分化(HR：0.592;952%CI:0.319-0.894。p = 0.044)為良性預(yù)后因素;NNMTh,神經(jīng)系統(tǒng)受累,TNM Ⅲ期或Ⅳ期和低分化腫瘤為不良預(yù)后。NNMTmRNA表達(dá)水平較高的胰腺癌細(xì)胞系CAPAN1,選取用于后續(xù)實(shí)驗(yàn)。經(jīng)實(shí)時(shí)定量PCR(RT-PCR)與western bloting(WB)檢測(cè)發(fā)現(xiàn),siRNA干擾實(shí)驗(yàn)組與對(duì)照組相比NNMT表達(dá)量顯著降低;Transwell測(cè)定siRNA干擾實(shí)驗(yàn)組處理的細(xì)胞在細(xì)胞活動(dòng)能力明顯減弱;MTT檢測(cè)siRNA干擾實(shí)驗(yàn)組凋亡率顯著高于對(duì)照組。結(jié)論:NNMTh與胰腺癌細(xì)胞凋亡顯著相關(guān)。這些結(jié)果表明NNMTh與NNMT1相比傾向于與胰腺癌患者不良的相關(guān)臨床病理特征。通過(guò)NNMT在胰腺癌組織、慢性胰腺炎組織與癌旁組織表達(dá)量比較,腺癌組織NNMT高表達(dá)率顯著高于癌旁組織與慢性胰腺炎組織。在有效驗(yàn)證與合理運(yùn)用下,NNMT表達(dá)可能成為區(qū)分慢性胰腺炎與胰腺癌的目標(biāo)靶分子。NNMTh與年齡較大(p = 0.014),較大腫瘤體積(p0.001),高級(jí)TNM分期(p0.001),腫瘤中低分化水平(p = 0.004),和CA19-9高表達(dá)水平(p = 0.005)顯著相關(guān)。這些結(jié)果表明NNMTh與NNMT1相比傾向于與胰腺癌患者不良的相關(guān)臨床病理特征。NNMT高表達(dá)可視為不良預(yù)后,此類(lèi)患者可能具有較短的生存期。
[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.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R735.9

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本文編號(hào)：1533465