生长抑素受体表达与肝细胞癌病理特征及预后的关系

Association between the expression of somatostatin receptors and pathological features,prognosis in hepatocellular carcinoma

目的研究生长抑素受体(SSTR)在肝细胞癌组织中表达水平及其与肝细胞癌临床病理特征及预后的关系。方法所有肝细胞癌标本取自2012年7月-2014年12月就诊于解放军第三医院及大连医科大学附属二院肝胆科行切除术后经病理组织学检查证实为HCC的患者(n=80,试验组),另选取同期疑似肝部疾病且行肝穿刺确诊的非肝细胞癌患者(n=80,对照组)。采用RT-PCR检测SSTR-2、SSTR-3 mRNA水平,采用免疫组化检测SSTR-2、SSTR-3蛋白表达的水平。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验,Kaplan-Meier法分析患者生存情况,Cox分析肝细胞癌患者预后的影响因素。结果对照组SSTR-2、SSTR-3 mRNA及蛋白均显著高于试验组(t值分别为6.456、8.128,χ2值分别为7.992、9.157,P值均<0.05)。单因素分析显示,SSTR-2和SSTR-3 mRNA与肿瘤结节(t=6.533、5.041,P值均<0.05)、分化程度(t=4.672、4.013,P值均<0.05)、浸润深度(t=6.735、7.019,P值均<0.05)、病毒性肝炎(t=4.929、4.535,P值均<0.05)、酒精性肝炎(t=4.032、4.362,P值均<0.05)、糖尿病(t=4.372、6.293,P值均<0.05)等显著相关;SSTR-2和SSTR-3蛋白与肿瘤结节(χ2=25.223、15.399,P值均<0.05)、分化程度(χ2=7.535、10.944,P值均<0.05)、浸润深度(χ2=22.520、9.968,P值均<0.05)密切相关。SSTR-2和SSTR-3阴性表达组的累积术后无瘤生存率明显低于SSTR-2和SSTR-3亚型的阳性表达组(P值分别为0.015、0.004),SSTR-2和SSTR-3阴性表达组的术后总体生存率明显低于SSTR-2和SSTR-3亚型的阳性表达组(P值分别为0.009、<0.001)。Cox模型分析显示,SSTR-2蛋白、SSTR-3蛋白、肿瘤结节数目、肝硬化、静脉浸润是HCC术后总生存期的独立危险因素(P值均<0.05)。结论SSTR-2和SSTR-3亚型在肝细胞癌组织中表达低于非肝细胞癌患者,其低表达与肝细胞癌的常见侵袭转移特征及不良预后密切相关。生长抑素受体可能成为肝细胞癌的预后标志物。

Objective To investigate the expression of somatostatin receptors（SSTRs） in hepatocellular carcinoma（HCC） tissue and its association with clinicopathological features and prognosis of HCC.Methods HCC samples were collected from 80 patients who visited Third Hospital of PLA and Department of Hepatobiliary Surgery in The Second Affiliated Hospital of Dalian Medical University and who underwent hepatectomy from July 2012 to December 2014 and were diagnosed with HCC based on postoperative pathology（trial group）.Another 80 patients who were suspected of liver disease and were not diagnosed with HCC by liver biopsy were enrolled as control group.RT-PCR and immunohistochemistry were used to measure the mRNA and protein expression of SSTR-2 and SSTR-3.The t-test was used for comparison of continuous data between groups,the chi-square test was used for comparison of categorical data between groups,the Kaplan-Meier method was used to analyze patients＇ survival,and the Cox regression analysis was used to investigate the influencing factors for the prognosis of HCC patients.Results The control group had significantly higher mRNA and protein expression of SSTR-2 and SSTR-3 than the trial group（t = 6.456 and 8.128,χ2= 7.992 and 9.157,all P〈0.05）.The univariate analysis showed that the mRNA expression of SSTR-2 and SSTR-3 was significantly correlated with tumor nodule（t = 6.533 and 5.041,both P〈0.05）,degree of tumor differentiation（t = 4.672 and 4.013,both P〈0.05）,depth of infiltration（t = 6.735 and 7.019,both P〈0.05）,viral hepatitis（t = 4.929 and4.535,both P〈0.05）,alcoholic hepatitis（t = 4.032 and 4.362,both P〈0.05）,and diabetes（t = 4.372 and 6.293,both P〈0.05）,and the protein expression of SSTR-2 and SSTR-3 was significantly correlated with tumor nodule（χ2= 25.223 and 15.399,both P〈0.05）,degree of tumor differentiation（χ2= 7.535 and 10.944,both P〈0.05）,and depth of infiltration（χ2= 22.520 and 9.968,both P〈0.05）.Compared with the group with positive expression of SSTR-2 and SSTR-3,the group with negative expression had significantly lower cumulative postoperative disease-free survival rate（P = 0.015 and 0.004） and postoperative overall survival rate（P = 0.009 and 0.001）.The Cox model analysis showed that protein expression of SSTR-2 and SSTR-3,the number of tumor nodules,liver cirrhosis,and vein infiltration in HCC tissue were independent risk factors for overall survival after HCC surgery（P〈0.05）.Conclusion HCC patients have lower expression of SSTR-2 and SSTR-3 than non-HCC patients,and such low expression is closely associated with invasion/metastasis and poor prognosis of HCC.SSTRs may be the markers for the prognosis of HCC.