胆管癌组织中信号转导及转录激活因子3信号通路相关基因的表达与意义

Expression and significance of signal transducers and activators of transcription 3 pathway genes in cholangiocarcinoma

    摘要
  • 摘要: 目的:探讨胆管癌组织中信号转导及转录激活因子3(STAT3)信号通路相关基因Survivin及环氧化酶2(COX -2)的表达及其与胆管癌患者临床病理特征和预后的关系。
    方法:收集2007年9月至2012年7月安徽医科大学附属省立医院收治的43例胆管癌患者的癌组织标本，收集同期行胆肠内引流术和胆管修复的12例肝内外胆管结石和胆管损伤患者的正常胆管组织标本作为对照。应用免疫组织化学染色检测胆管癌及正常胆管组织中STAT3、磷酸化STAT3(p STAT3)、Survivin及COX -2蛋白的表达，并分析其与胆管癌患者临床病理特征和预后的关系。采用门诊或电话方式对胆管癌患者进行随访，随访时间截至2014年3月。计数资料采用χ2检验，相关性分析采用Spearman检验。采用Kaplan Meier法绘制生存曲线，生存分析采用Log rank检验。
    结果:STAT3、p STAT3、Survivin、COX -2蛋白在胆管癌组织中阳性表达率分别为69.8%(30/43)、65.1%(28/43)、72.1%(31/43)、79.1%(34/43)，在正常胆管组织中阳性表达率分别为41.7%(5/12)、8.3%(1/12)、16.7%(2/12)、41.7%(5/12)。p STAT3、Survivin、COX -2蛋白在胆管癌组织中的阳性表达率显著高于正常胆管组织，两组比较，差异有统计学意义(χ2=12.136，9.811，4.679，P<0.05)。p STAT3、Survivin、COX -2蛋白在胆管癌组织中的高表达与肿瘤局部浸润转移有关(χ2=14.700，5.959，4.075，P<0.05)；p STAT3蛋白阳性表达与肿瘤神经侵犯有关(χ2=10.384，P<0.05)；Survivin、COX -2蛋白表达与胆管癌患者肿瘤神经侵犯无关(χ2=2.718，3.024，P>0.05)；p STAT3、Survivin、COX -2蛋白表达与胆管癌患者性别、年龄、肿瘤位置、分化程度、肿瘤直径无关(χ2=0.148，0.720，1.835，1.040，0.236;0.001，0.009，0.029，1.863，0.197;0.433，0.686，0.002，2.974，0.029，P>0.05)。Survivin及COX -2蛋白的表达与p STAT3呈正相关(r=0.524，0.583，P<0.05)。43例胆管癌患者获得随访，随访时间为6个月至5年。在43例胆管癌组织中，肝门部胆管癌17例，p STAT3、Survivin、COX -2蛋白表达阳性者的中位生存时间分别为7、9、9个月，p STAT3、Survivin、COX -2蛋白表达阴性者的中位生存时间分别为18、11、11个月。p STAT3蛋白表达阳性和阴性患者的生存率分别为33.3%和68.6%，两者比较，差异有统计学意义(χ2=12.916，P<0.05)。在26例胆总管中下段癌组织中，p STAT3、Survivin、COX -2蛋白表达阳性者的中位生存时间分别为9、10、9个月，p STAT3、Survivin、COX -2蛋白表达阴性者的中位生存时间分别为20、20、20个月。p STAT3、Survivin、COX -2蛋白表达阳性患者的生存率分别为20.8%、9.4%和8.5%，显著低于p STAT3、Survivin、COX -2蛋白表达阴性患者的37.5%、37.5%和50.0%(χ2=12.787，6.245，11.161， P<0.05)。
    结论:p STAT3、Survivin、COX -2蛋白在胆管癌中表达增高，且3者表达具有相关性。Survivin及COX -2可能是STAT3信号通路在胆管癌中影响肿瘤发生、发展及预后的效应基因。

     

    Abstract: Objective:To investigate the expression of STAT3 signaling pathway genes including Survivin and COX -2 in cholangiocarcinoma,as well as the relationship between expression of these genes and prognosis of patients with cholangiocarcinoma.
    Methods:The tumor and normal tissue samples were respectively collected from 43 patients with cholangiocarcinoma and 12 patients with intra and extrahepatic bile duct stones or hepatic duct injury in the Affiliated Provincial Hospital of Anhui Medical University from September 2007 to July 〖HJ*8〗2012.
    The expression of STAT3, phosphorylated STAT3 (p STAT3), Survivin and COX -2 were examined using immunohistochemistry, and the relationship between the expression of these genes and the clinical pathological features and prognosis of patients with cholangiocarcinoma was analyzed. Patients were followed up through outpatient examination and telephone interview until March 2014. Categorical data were analyzed using the chi square test. Correlation analysis was done by Spearman′s method. The survival curve was generated using the Kaplan Meier method, and the survival analysis was conducted using the log rank test.
    Results:The positive expression rates of STAT3, p STAT3, Survivin and COX -2 in the tumor samples were 69.8%(30/43), 65.1%(28/43), 72.1%(31/43), 79.1%(34/43), respectively, which were compared with 41.7%(5/12), 8.3%(1/12), 16.7%(2/12) and 41.7%(5/12) in the normal tissue samples, showing a significant difference for the last 3 indexes (χ2=12.136, 9.811, 4.679, P<0.05 ). Overexpression of p STAT3, Survivin and COX -2 protein was correlated with lymph node metastasis (χ2=14.700, 5.959, 4.075, P<0.05). Overexpression of p STAT3 was also related to neural invasion (χ2=10.384, P<0.05). Expression of Survival and COX -2 protein was not associated with lymph invasion (χ2=2.718, 3.024, P>0.05). Expression of p STAT3, Survivin and COX -2 was however not associated with gender, age and tumor location, differentiation and diameter (χ2=0.148, 0.720, 1.835, 1.040, 0.236; 0.001, 0.009, 0.029, 1.863, 0.197; 0.433, 0.686, 0.002, 2.974, 0.029, P>0.05). Expression of Survivin and COX -2 protein was positively correlated to p STAT3 protein (r=0.524, 0.583, P<0.05). All the 43 patients were followed up for 6 -60 months. Among the 17 patients with hilar cholangiocarcinoma, the median survival time was 7, 9, 9 months for patients with positive expression of p STAT3, Survivin and COX -2 protein, compared with 18, 11 and 11 months for patients with negative expression of these proteins. The survival rates of the patients with positive and negative expression of p STAT3 protein were 33.3% and 68.6%, respectively, with a statistical significance for p STAT3 protein (χ2=12.916, P<0.05). Of the remaining 26 patients with common bile duct carcinoma, the median survival time was 9, 10 and 9 months for patients with positive expression of p STAT3, Survivin and COX -2 protein, compared with 20, 20 and 20 months for patients with negative expression of these proteins.The survival rates of the patients with positive expression of p STAT3, Survivin and COX -2 protein were 20.8%, 9.4% and 8.5%, which were lower than 37.5%, 37.5% and 50.0% of patients with the negative expression of these proteins, with a statically significance for all the 3 proteins (χ2=12.787, 6.245, 11.161, P<0.05).
    Conclusion:The p STAT3, Survivin, COX -2 proteins are highly expressed in the cholangiocarcinoma and the expression levels of these proteins are positively correlated. The survivin and COX -2 may be the downstream genes of STAT signaling pathway, which are involved in the progression and prognosis of cholangiocarcinoma.

     

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