神经前体细胞表达发育下调蛋白4-1在胰腺癌组织中的表达和临床意义

Expression of neural precursor cell expressed developmentally downregulated 4-1 in pancreatic cancer tissue and its clinical significance

目的探讨泛素化E3连接酶神经前体细胞表达发育下调蛋白4-1(NEDD4-1)在胰腺癌组织中的表达及临床意义。方法选取2017年1月—2019年12月于徐州市中心医院行手术治疗的病理学检查确诊为胰腺导管腺癌患者58例。采用免疫组化法检测胰腺癌组织标本中NEDD4-1的表达情况,分析NEDD4-1的表达与胰腺癌临床病理特征的相关性。使用Western Blot检测正常胰腺导管上皮HPDE6-C7细胞及胰腺癌SW1990、BxPC-3、PANC-1细胞中NEDD4-1的表达水平。计量资料两组间比较采用t检验。计数资料两组间比较采用χ^(2)检验。采用Kaplan-Meier检验绘制生存曲线,log-rank检验进行生存分析。采用Cox回归分析预后相关因素。结果NEDD4-1在胰腺癌组织里的表达水平较癌旁组织中明显升高(79.31%vs 19.05%,χ^(2)=35.614,P=0.001),且NEDD4-1在胰腺癌细胞株中的蛋白表达水平较正常胰腺导管上皮细胞明显上调(P值均<0.01)。NEDD4-1的表达分别与胰腺癌患者的远处转移、肿瘤分化程度和肿瘤TNM分期相关(χ^(2)值分别为5.089、9.071、8.882,P值分别为0.04、0.003、0.003)。NEDD4-1阳性表达患者的平均存活时间明显短于阴性表达患者[(13.61±0.95)个月vs(22.22±2.20)个月,P=0.001]。Cox回归分析结果显示,NEDD4-1表达(HR=2.312,95%CI:1.010~5.295,P=0.047)、淋巴结转移(HR=2.981,95%CI:1.556~5.712,P=0.001)及肿瘤分化程度(HR=2.144,95%CI:1.155~3.979,P=0.016)为胰腺癌患者预后的独立危险因素。结论NEDD4-1在胰腺癌组织及细胞内的阳性表达明显升高,且NEDD4-1阳性表达与预后不良相关,或可作为胰腺癌预后的一个预测因子和潜在治疗靶点。

Objective To investigate the expression of the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-1(NEDD4-1)in pancreatic cancer tissue and its clinical significance.Methods Clinical data were collected from 58 patients who underwent surgical treatment in Xuzhou Central Hospital from January 2017 to December 2019 and were diagnosed with pancreatic ductal adenocarcinoma based on pathological examination.Immunohistochemistry was used to measure the expression of NEDD4-1 in pancreatic cancer tissue samples,and the association between the expression of NEDD4-1 and the clinicopathological features of pancreatic cancer was analyzed.Western blot was used to measure the protein expression level of NEDD4-1 in normal pancreatic ductal epithelial HPDE6-C7 cells and pancreatic cancer SW1990,BxPC-3,and PANC-1 cells.The t-test was used for comparison of continuous data between two groups,and the chi-square test was used for comparison of categorical data between two groups.The Kaplan-Meier method was used to plot survival curves,and the log-rank test was used for survival analysis.The Cox proportional-hazards regression model was used to investigate the factors associated with prognosis.Results The expression level of NEDD4-1 in pancreatic cancer tissue was significantly higher than that in adjacent tissue(79.31%vs 19.05%,χ^(2)=35.614,P<0.01),and the protein expression of NEDD4-1 in pancreatic cancer cells was significantly higher than that in normal pancreatic ductal epithelial cells(P<0.01).In the patients with pancreatic cancer,the expression of NEDD4-1 was associated with distant metastasis(χ^(2)=5.089,P=0.040),tumor differentiation(χ^(2)=9.071,P=0.003),and TNM stage(χ^(2)=8.882,P=0.003).The patients with high NEDD4-1 expression had a significantly shorter mean survival time than those with low expression(13.61±0.95 months vs 22.22±2.20 months,P=0.001).The Cox regression analysis showed that NEDD4-1 expression(hazard ratio[HR]=2.312,95%confidence interval[CI]:1.010-5.295,P=0.047),degree of tumor differentiation(HR=2.981,95%CI:1.556-5.712,P=0.001),and lymph node metastasis(HR=2.144,95%CI:1.155-3.979,P=0.016)were independent risk factors for the prognosis of patients with pancreatic cancer.Conclusion There is a significant increase in the expression of NEDD4-1 in pancreatic cancer tissue and cells,and the high expression of NEDD4-1 is associated with poor prognosis.Therefore,it can be used as a prognostic biomarker and a therapeutic target for pancreatic cancer.