胰腺癌中P53通路相关蛋白的表达及其临床意义

背景与目的:P53通路在胰腺癌的发生发展中发挥重要作用,然而关于此通路是如何启动、如何作用的研究较少,故本研究探讨P53通路相关基因(ATM/P53/Mdm2/P21WAF/CIP1)蛋白在167例胰腺癌发生、发展中及与预后的关系。方法:应用组织芯片和免疫组化法研究ATM、P53、Mdm2和P21WAF/CIP1在167例胰腺外分泌恶性肿瘤和101例癌旁组织以及11例胰腺良性病变中的表达情况。结果:ATM、P53、Mdm2和P21WAF/CIP1在癌组织中的阳性率分别为67.7%、57.5%、64.1%和39.5%,在非癌组织中阳性率分别为82.1%、6.3%、5.4%和71.4%。与非癌组织相比,癌组织中P53和Mdm2表达明显升高(P<0.01),而ATM和P21WAF/CIP1的表达明显降低(P<0.05)。P21WAF/CIP1的阳性表达与发病年龄、神经受累显著相关(P<0.05);P53的阳性表达与肿瘤的分化、淋巴结转移和神经受累均显著相关(P<0.05);Mdm2的阳性表达与肿瘤的分化显著相关(P<0.05);ATM的阳性表达与年龄相关(P<0.05);四者阳性表达两两之间统计学上具有关联性(P<0.05)。44例获1年以上随访者中ATM /Mdm2 /P53 P21WAF/CIP1 、ATM-/Mdm2-/P53-/P21WAF/CIP1-、ATM Mdm2 /P53 分别为9、11、5例,平均生存期依次为9.3、26.1、20月。Kaplan-Meier分析显示全阳性组预后较全阴性组和P21阴性组预后差。结论:P53和Mdm2的过表达以及ATM和P21WAF/CIP1的缺失表达可能会导致胰腺癌的形成和进展;4种蛋白可能以ATM-P53-Mdm2-P21WAF/CIP1通路的方式作用于细胞的转化和肿瘤的形成;联合检测P53和Mdm2的表达可用于评定胰腺癌的恶性程度。

Expression and clinical significance of P53 pathway-associated proteins in pancreatic carcinoma

BACKGROUND & OBJECTIVE: P53 pathway plays a critical role in carcinogenesis of pancreatic carcinoma. However, its trigger and function mechanisms have seldom been reported. This study was to investigate the expression and clinical significance of P53 pathway-related proteins ATM, P53, Mdm2, and P21WAF/CIP1 in pancreatic carcinoma. METHODS: The expression of ATM, P53, Mdm2, and P21WAF/CIP1 proteins in 167 specimens of pancreatic carcinoma and 112 specimens of non-cancer pancreatic tissues was detected by tissue microarray and immunohistochemistry. RESULTS: The positive rates of P53 and Mdm2 were higher in pancreatic carcinoma than in non-tumor pancreatic tissues (57.5% vs. 6.3%, 64.1% vs. 5.4%, P<0.01), while the positive rates of ATM and P21WAF/CIP1 were lower in pancreatic carcinoma than in non-tumor pancreatic tissues (67.7% vs. 82.1%, 39.5% vs. 71.4%, P<0.05). ATM expression in pancreatic carcinoma was related to patients' age (P<0.05). P53 expression was related to tumor differentiation, lymph node metastasis, and nerve involvement (P<0.05). Mdm2 expression was related to tumor differentiation (P<0.05). P21WAF/CIP1 expression was related to patients' age and nerve involvement (P<0.05). There were statistical correlations between these 4 proteins (P<0.05). CONCLUSIONS: Overexpression of P53 and Mdm2 and loss of ATM and P21WAF/CIP1 expression may contribute to the tumorigenesis and development of pancreatic carcinoma. The 4 proteins may affect cell transformation and tumorigenesis through ATM-Mdm2-P53-P21WAF/CIP1 pathway. Co-detection of P53 and Mdm2 can be used to evaluate the differentiation of pancreatic carcinoma.