胰腺癌p53上下游基因mdm2、p21WAF/CIP1以及P14ARF蛋白的表达及相互关系

目的 探讨p14ARF、p53、mdm2及p21WAF/CIP1蛋白在胰腺癌组织中的表达、相互关系及意义。方法 选取167例胰腺癌、101例癌旁与13例良性病变组织构建组织芯片(又称组织微阵列),应用免疫组织化学EnVision二步法检测这4种蛋白在胰腺良恶性病变中的表达。结果 p14ARF、p53、mdm12及p21WAF/CIP1在胰腺癌中表达的阳性率分别为35.3％(59/167)、57.5％(96/167)、64.1％(107/167)和39.5％(66/167)。同癌旁组织相比,p53和mdm2表达明显升高(P<0.01),而p14ARF和p21WAF/CIP1的表达明显降低(P<0.05)。p21WAF/CIP1的阳性表达与年龄、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);p14ARF与年龄和浸润转移显著相关(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)。结论 p53和mdm2的过表达以及p14ARF和p21WAF/CIP1的缺失表达可能会导致胰腺癌的形成和进展;4种蛋白主要以p14ARF-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 of proteins in p53 (p14ARF-mdm2-p53-p21WAF/CIP1) pathway and their significance in exocrine pancreatic carcinoma

Objective To investigate the expression of p14ARF, p53, mdm2 and p21WAF/CIP1 proteins and their relationship in exocrine pancreatic carcinoma. Methods Specimens of pancreatic carcinoma, adjacent non-neoplastic pancreatic tissue and pancreatic benign lesions were examined for p14ARF, p53, mdm2 and p21WAF/CIP1 protein expression by tissue microarray technique and immunohistochemistry. ResultsThe expression of p14ARF, p53, mdm2 and p21WAF/CIP1 proteins in pancreatic carcinoma were 35. 3% (59/167) , 57. 5% (96/101 ) , 64. 1% (107/167) and 39. 5% (66/167) respectively. The expression of p53 proteins was increased in pancreatic carcinoma (P < 0. 01 ) , while the expression of p14ARF and p21WAF/CIP1 proteins was reduced (P < 0. 05) , as compared with that in non-neoplastic pancreatic tissue. p21WAF/CIP1 protein expression pancreatic carcinoma significantly correlated with the age of patients and perineural invasion ( P < 0. 05 ). p53 protein expression correlated significantly with tumor differentiation, lymph node metastasis and perineural invasion (P < 0. 05). Mdm2 protein expression correlated significandy with tumor differentiation (P < 0. 05) , while p14ARF protein expression correlated significantly with the age of patients and metastasis ( P < 0. 05). There was also statistic correlation between the expression of these four genes (P < 0. 05). Conclusions Overexpression of p53 and mdm2 and loss of p14ARF and P21WAF/C1P1 expression may contribute to the pathogenesis of pancreatic carcinoma. These proteins play a critical role in cell cycle arrest and apoptosis after DNA damage through p14ARF-mdm2-p53-p21WAF/CIP1 pathway. Detection of p53 and Mdm2 protein overexpression may be useful in evaluation of the aggressiveness of pancreatic carcinoma.