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合并与未合并糖尿病的胰腺癌患者血管生成素样蛋白2在血清中的表达及其与预后的关系
DOI: 10.3969/j.issn.1001-5256.2021.06.034
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：秦雯负责课题设计，资料分析，撰写论文；陈泰文、郑海平参与收集数据和样本，进行统计分析；黄夏宁负责血清ELISA测定血清ANGPTL2浓度的实验操作及统计学分析；朱小东指导撰写文章并最后定稿。
Serum expression of angiopoietin-like protein 2 in pancreatic cancer patients with or without diabetes and its association with prognosis
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摘要:
目的 探讨血管生成素样蛋白2(ANGPTL2)在合并与未合并糖尿病的胰腺癌患者中的表达水平及其作为胰腺癌患者预后指标的价值。 方法 收集2015年1月—2018年1月于广西医科大学第一附属医院、广西医科大学附属肿瘤医院、广西医科大学附属武鸣医院治疗的胰腺癌患者的血清标本125例，其中单纯胰腺癌组64例、合并糖尿病胰腺癌组61例，另选取66例健康体检者作为对照组。采用ELISA法检测各组血清ANGPTL2水平，分析ANGPTL2的表达水平与临床指标、生存预后的关系。符合正态分布的计量资料3组间比较采用单因素方差分析，进一步两两比较采用Bonferroni法；偏态分布者的计量资料3组间比较采用独立样本Kruskal-Wallis H秩和检验，进一步两两比较采用单因素ANOVA法。计数资料组间比较采用χ2检验。相关性分析采用Spearman相关分析。Kaplan-Meier法绘制生存曲线，log-rank检验比较生存率。采用Cox风险模型行单/多因素分析，确定影响胰腺癌预后的独立危险因素。 结果 合并糖尿病胰腺癌组患者血清ANGPTL2[7.79(7.12~8.17) ng/ml]明显高于单纯胰腺癌组[5.74(5.08~6.40) ng/ml]和健康对照组[3.72(3.25~4.16) ng/ml](P值均＜0.001)。血清ANGPTL2水平与CA19-9、CEA均呈正相关(r值分别为0.560、0.731，P值均＜0.001)。单因素分析显示，肿瘤大小、远处器官转移、分化程度、CEA、ANGPTL2、HbA1c与胰腺癌患者远期生存密切相关(P值均＜0.05)；多因素分析显示，肿瘤大小(HR=2.657，P=0.005)、远处器官转移(HR=5.000，P=0.014)、分化程度(HR=2.466, P=0.004)、CEA(HR=1.110，P＜0.001)、ANGPTL2(HR=1.901，P=0.001)均为影响胰腺癌患者预后的独立危险因素。在所有胰腺癌患者中，ANGPTL2高表达组的2年生存率明显低于ANGPTL2低表达组(8.51% vs 25.81%，χ2=5.651，P=0.017)。在合并糖尿病的胰腺癌患者中ANGPTL2高表达组的2年生存率也明显低于ANGPTL2低表达组(2.20% vs 32.70%, χ2=24.895，P＜0.001)。 结论 ANGPTL2可能是评价胰腺癌患者，特别是合并糖尿病的胰腺癌患者预后的有效指标。 Abstract:Objective To investigate the expression level of angiopoietin-like protein 2 (ANGPTL2) in pancreatic cancer patients with or without diabetes and the clinical value of ANGPTL2 as a prognostic marker in patients with pancreatic cancer. Methods Serum samples were collected from 125 pancreatic cancer patients who were treated in The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University Cancer Hospital, and Wuming Hospital of Guangxi Medical University from January 2015 to January 2018, among whom 64 had pancreatic cancer alone and 61 had pancreatic cancer and diabetes, and 66 individuals who underwent physical examination were enrolled as control group. ELISA was used to measure the serum level of ANGPTL2, and the association of the expression level of ANGPTL2 with clinical indices, survival, and prognosis was analyzed. A one-way analysis of variance was used for comparison of normally distributed continuous data between three groups, and the Bonferroni test was used for comparison between two groups. The independent-samples Kruskal-Wallis H test was used for comparison of continuous data with skewed distribution between three groups and the one-way ANOVA analysis was used for comparison between two groups. The chi-square test was used for comparison of categorical data between groups. Spearman correlation analysis was also performed to investigate correlation. The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used for comparison of survival rate. The Cox risk model was used to perform univariate and multivariate analyses to determine independent risk factors for the prognosis of pancreatic cancer. Results The pancreatic cancer+diabetes group had a significantly higher serum concentration of ANGPTL2 than the pancreatic cancer group and the control group [7.79 (7.12-8.17) ng/ml vs 5.74 (5.08-6.40) ng/ml and 3.72 (3.25-4.16) ng/ml, χ2=126.367, P < 0.001]. Serum ANGPTL2 concentration was positively correlated with carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) (r=0.560 and 0.731, both P < 0.001). The univariate analysis showed that tumor size, distant organ metastasis, degree of tumor differentiation, CEA, ANGPTL2, and HbA1c were closely associated with the long-term survival of pancreatic cancer patients, and the multivariate analysis showed that tumor size (HR=2.657, P=0.005), distant organ metastasis (HR=5.000, P=0.014), degree of tumor differentiation (HR=2.466, P=0.004), CEA(HR=1.110, P < 0.001) and ANGPTL2(HR=1.901, P=0.001) were independent risk factors for the prognosis of pancreatic cancer patients. For all pancreatic cancer patients, the high ANGPTL2 expression group had a significantly lower 2-year survival rate than the low ANGPTL2 expression group (8.51% vs 25.81%, χ2=5.651, P=0.017). For the pancreatic cancer patients with diabetes, the high ANGPTL2 expression group had a significantly lower 2-year survival rate than the low ANGPTL2 expression group (2.20% vs 32.70%, χ2=24.895, P < 0.001). Conclusion ANGPTL2 can be used as an effective clinical index to evaluate the prognosis of pancreatic cancer patients, especially those with diabetes. -
Key words:
- Pancreatic Neoplasms /
- Diabetes Mellitus /
- Angiopoietins /
- Prognosis
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表 1 3组一般资料比较
项目 单纯胰腺癌组(n=64) 合并糖尿病胰腺癌组(n=61) 健康对照组(n=66) 统计值 P值 年龄(岁) 63.08±8.25 61.00±8.23 62.91±8.78 F=1.166 0.314 性别(男/女) 35/29 34/27 36/30 χ2=0.021 0.989 BMI(kg/m2) 24.29±1.92 23.40±2.05 25.16±2.00 F=12.371 ＜0.001 HbA1c(%) 5.50±0.29 8.28±0.59 5.27±0.16 F=119.6 ＜0.001 CRP(mg/dl) 1.61±0.68 1.85±0.621) 0.25±0.12 F=170.022 ＜0.001 TC(mg/dl) 178.17±22.61 167.78±22.661)2) 186.00±22.34 F=10.394 ＜0.001 TG(mg/dl) 119.59±28.62 122.67±26.431) 97.59±25.55 F=16.696 ＜0.001 注：1)与健康对照组比较，P＜0.05；2)与单纯胰腺癌组比较，P＜0.05。 
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表 2 3组人群血清CEA、CA19-9及ANGPTL2水平比较
组别 例数 CEA(ng/ml) CA19-9(U/ml) ANGPTL2(ng/ml) 单纯胰腺癌组 64 14.71(9.07~24.07) 83.11(40.85~109.77) 5.74(5.08~6.40) 合并糖尿病胰腺癌组 61 30.43(18.99~37.12) 130.45(98.62~214.01) 7.79(7.12~8.17) 健康对照组 66 2.01(1.42~2.93) 13.08(9.03~19.60) 3.72(3.25~4.16) χ2值 135.7011) 114.5181) 126.3671) P值 ＜0.001 ＜0.001 ＜0.001 注: 组间两两比较，1)P值均＜0.05。
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表 3 影响胰腺癌患者远期生存的单因素分析
因素 β HR 95%CI P值 肿瘤大小 1.126 3.084 1.504~6.324 0.002 血管侵犯 -0.571 0.565 0.210~1.520 0.258 神经侵犯 -0.015 0.985 0.374~2.595 0.975 淋巴结转移 0.826 2.283 0.904~5.765 0.081 远处器官转移 1.719 5.577 1.472~21.135 0.011 分化程度 0.928 2.530 1.347~4.752 0.004 CA199(U/ml) 0.000 1.000 0.994~1.006 0.912 CEA(ng/ml) 0.131 1.140 1.070~1.215 ＜0.001 CRP(mg/dl) -0.353 0.703 0.356~1.389 0.310 ANGPTL2(ng/ml) 0.584 1.793 1.224~2.628 0.003 HbA1c(%) 0.653 1.903 1.354~2.873 0.003
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表 4 影响胰腺癌患者远期生存的多因素分析
因素 HR 95%CI P值 肿瘤大小 2.657 1.338~5.276 0.005 远处器官转移 5.000 1.380~18.114 0.014 分化程度 2.466 1.344~4.522 0.004 CEA 1.110 1.056~1.167 ＜0.001 ANGPTL2 1.901 1.310~2.759 0.001
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表 5 血清ANGPTL2表达水平、是否合并糖尿病与胰腺癌患者预后的关系
参数 例数 2年生存率(%) χ2值 P值 ANGPTL2 5.651 0.017 高表达组 94 8.51 低表达组 31 25.81 HbA1c 0.621 0.431 升高 61 8.20 正常 64 12.50
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