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Numb、MDM2和p53在胰腺癌中表达的相关性及临床病理学意义

The relationship and clinicopathological significance of Numb, MDM2 and p53 expression in human pancreatic cancer

摘要:

目的 探讨胰腺导管腺癌(PDAC)中Numb、MDM2和p53表达相关性及临床病理学意义.方法 应用免疫组化法检测65例配对的PDAC及癌旁组织石蜡标本中Numb、MDM2和p53蛋白表达情况,观察三者表达相关性及与患者临床病理学参数的关系;再以Western blot法检测16对配对新鲜PDAC组织及癌旁组织中三者的表达水平.通过免疫荧光法、Western blot法和实时定量(qRT)-PCR法检测Numb在不同分化的胰腺癌细胞株Capan-2、PANC-1及AsPC-1中的表达.分别采用配对t检验、x2检验、Kaplan-Meier、Cox回归分析等统计学方法分析实验结果.结果 免疫组化检测结果显示,Numb在PDAC及配对癌旁组织中表达差异无统计学意义(t=1.746,P=0.086);MDM2和p53在PDAC中表达高于癌旁组织(t=3.294,P=0.002;t=3.152,P=0.002);Numb表达与肿瘤大小(x2=5.206,P=0.023)、分化程度(x2=7.802,P=0.005)及UICC分期(x2=4.770,P=0.029)呈负相关;MDM2和p53表达分别与胰腺癌T及UICC分期呈正相关(x2=5.182,P=0.023;x2=6.448,P=0.011).相关性分析结果显示,Numb与MDM2呈负相关(r=-0.283,P=0.023),但他们与p53表达无明显相关性(P>0.05).单因素和多因素分析结果显示,Numb是影响胰腺癌患者预后的一个保护因素(x2=5.408,P=0.020),并且Numb阳性和MDM2阴性表达的胰腺癌患者预后更好(x2=5.868,P=0.015).Western blot检测结果显示,Numb在8例高分化PDAC中蛋白表达高于配对的癌旁组织(t=1.092,P=0.020),而MDM2和p53在16例PDAC中呈明显高表达(t=3.263,P=0.005;t=3.607,P=0.003).免疫荧光、Western blot和qRT-PCR检测结果显示,随着胰腺癌细胞分化程度增高,Numb荧光强度、蛋白和mRNA表达水平逐渐增强.结论 Numb在胰腺癌发生发展中主要充当一个抑癌基因的角色,Numb、MDM2和p53可能共同参与胰腺癌的发生进展.

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abstracts:

Objective To study the relationship and clinicopathological significance of Numb,MDM2 and p53 expression in human pancreatic cancer.Methods The expression of Numb,MDM2 and p53 proteins in 65 cases of paired paraffin embedded pancreatic ductal adenocarcinoma (PDAC) specimens and adjacent non-cancerous pancreas was detected by immunohistochemistry (IHC).The relationship among their expression and clinicopathological characters was analyzed.Westem blot was used to examine their expression in 16 paired fresh PDAC specimens and adjacent non-cancerous pancreatic tissues.Meanwhile,Numb expression in Capan-2,PANC-1 and AsPC-1 pancreatic cancer cells with different differentiation were detected by immunofluorescence (IF),Westem blot and quantitative real-time (qRT)-PCR,respectively.Paired sample t-test,x2 test,Kaplan-Meier and Cox regression were used to analyze the results of our experiments,respectively.Results IHC showed that there was no differential expression of Numb in PDAC and adjacent pancreas (t =1.746,P =0.086),while the expression of MDM2 and p53 was significantly increased in PDAC,compared to that in paired normal pancreas (t =3.294,P =0.002 ; t =3.152,P =0.002,respectively).Numb expression was negatively associated with tumor size (x2 =5.206,P =0.023),differentiation (x2 =7.802,P =0.005) and UICC stage (x2 =4.770,P =0.029),while expression of MDM2 and p53 was positively associated with tumor T and TNM stage,respectively (x2 =5.182,P =0.023 ; x2 =6.448,P =0.011).Correlation analysis showed a negative association between Numb and MDM2(r =-0.283,P =0.023),but there was no relationship of them with p53(P >0.05).Univariate and multivariate analysis revealed that Numb was a protective prognostic indicator for patients with PDAC (x2 =5.408,P =0.020).Moreover,patients with Numb positive and MDM2 negative expression had a significantly better overall survival(x2 =5.868,P =0.015).Western blot showed that Numb expression was much higher in well differentiated PDAC than that in paired normal pancreas (t =1.092,P =0.020),while the expression of MDM2 and p53 was significantly increased in 16 cases of PDAC(t =3.263,P =0.005 ;t =3.607,P =0.003,respectively).Numb expression was gradually increased in pancreatic cancer cells with the increasing degree of cell differentiation detected by IF,Westem blot and qRT-PCR.Conclusions Numb acts as a tumor suppressor gene in the development of PDAC.Numb,MDM2 and p53 might coordinately participate in the development of PDAC.

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作者: 盛伟伟 [1] 董明 [1] 周建平 [1] 李新 [1] 柳青峰 [2] 董齐 [2] 李丰 [3]
第一作者: 盛伟伟
期刊: 《中华外科杂志》2014年52卷9期 675-681页 MEDLINEISTICPKUCSCD
栏目名称: 论著
DOI: 10.3760/cma.j.issn.0529-5815.2014.09.011
发布时间: 2014-09-25
基金项目:
辽宁省教育厅科研资助项目 辽宁省科学事业公益研究基金资助项目
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