血管内皮生长因子和X盒结合蛋白1表达与脑胶质瘤患者肿瘤微血管密度及预后的关系

Correlations of vascular endothelial growth factor and X-box binding protein 1 with microvascular density and prognosis of glioma patients

目的观察脑胶质瘤患者癌组织血管内皮生长因子(VEGF)、X盒结合蛋白1(XBP1)表达情况,探讨其与肿瘤微血管密度及预后的关系。方法2018年6月—2020年12月南阳市第二人民医院、南阳医学高等专科学校第一附属医院、南阳市中心医院诊治脑胶质瘤患者200例,均行开颅肿瘤切除术,术中收集癌组织和癌旁组织,采用实时荧光定量PCR法检测VEGF、XBP1 mRNA相对表达量,采用免疫组织化学法检测肿瘤微血管密度,比较癌组织与癌旁组织VEGF、XBP1 mRNA相对表达量,不同临床病理特征患者癌组织VEGF、XBP1 mRNA相对表达量及肿瘤微血管密度;采用多因素Cox回归分析脑胶质瘤患者预后不良的影响因素;采用Pearson相关法分析脑胶质瘤患者癌组织VEGF、XBP1 mRNA相对表达量与肿瘤微血管密度的相关性。200例患者根据癌组织VEGF、XBP1 mRNA相对表达量及肿瘤微血管密度中位数分为VEGF高表达组(VEGF mRNA相对表达量≥6.34)107例和VEGF低表达组(VEGF mRNA相对表达量<6.34)93例、XBP1高表达组(XBP1 mRNA相对表达量≥5.65)103例和XBP1低表达组(XBP1 mRNA相对表达量<5.65)97例、高肿瘤微血管密度组(肿瘤微血管密度≥33.85)101例和低肿瘤微血管密度组(肿瘤微血管密度<33.85)99例,随访3年,绘制Kaplan-Meier生存曲线,比较VEGF、XBP1高、低表达组及高、低肿瘤微血管密度组3年总生存率。结果脑胶质瘤患者癌组织VEGF、XBP1 mRNA相对表达量(6.34±0.96、5.65±1.06)均高于癌旁组织(1.03±0.11、1.05±0.16)(t=77.715,P<0.001;t=60.684,P<0.001)。病理分级Ⅲ~Ⅳ级(6.66±0.87、5.93±0.89)、低分化(6.76±0.75、6.12±0.99)的脑胶质瘤患者癌组织VEGF、XBP1 mRNA相对表达量均高于病理分级Ⅰ~Ⅱ级(6.04±0.94、5.40±1.13)、中高分化(6.15±0.98、5.44±1.02)者(t=4.767,P<0.001;t=3.666,P<0.001;t=4.738,P<0.001;t=4.399,P<0.001),≥50岁、病理分级Ⅲ~Ⅳ级的脑胶质瘤患者肿瘤微血管密度(35.45±7.99、35.77±7.27)均高于<50岁、病理分级Ⅰ~Ⅱ级者(32.08±7.80、32.04±8.37)(t=3.009,P=0.003;t=3.361,P=0.001)。病理分级(HR=1.730,95%CI:1.427~3.154,P=0.008)、VEGF(HR=1.185,95%CI:1.027~1.514,P<0.001)和XBP1(HR=1.178,95%CI:1.016~1.431,P=0.009)mRNA相对表达量、肿瘤微血管密度(HR=1.042,95%CI:1.009~1.226,P=0.023)是脑胶质瘤患者预后不良的影响因素。脑胶质瘤患者癌组织VEGF、XBP1 mRNA相对表达量与肿瘤微血管密度均呈正相关(r=0.355,P<0.001;r=0.292,P<0.001)。VEGF高表达组、XBP1高表达组、高肿瘤微血管密度组3年总生存率(13.08%、15.53%、15.84%)分别低于VEGF低表达组、XBP1低表达组、低肿瘤微血管密度组(68.82%、63.92%、62.63%)(χ^(2)=62.518,P<0.001;χ^(2)=47.019,P<0.001;χ^(2)=39.034,P<0.001)。结论VEGF、XBP1在脑胶质瘤患者癌组织中呈高表达,其表达与肿瘤病理分级、分化程度有关,与肿瘤微血管密度呈正相关;病理分级Ⅲ~Ⅳ级及VEGF、XBP1表达、肿瘤微血管密度增高的脑胶质瘤患者预后不良风险较大。

Objective To observe the expressions of vascular endothelial growth factor(VEGF)and X-box binding protein 1(XBP1)in glioma tissues,and to explore their relationships with glioma microvascular density(MVD)and prognosis.Methods Totally 200 patients with glioma underwent craniotomy to remove glioma in the Second People's Hospital of Nanyang,the First Affiliated Hospital of Nanyang Medical College,and Nanyang Central Hospital from June 2018 to December 2020.The specimens of glioma tissues and paracancerous tissues were collected during operation.Real-time fluorescence quantitative PCR was used to detect the relative expressions of VEGF and XBP1 mRNAs.Immunohistochemistry was used to detect the MVD.The relative expressions of VEGF and XBP1 mRNAs were compared between glioma tissues and paracancerous tissues,and the relative expressions of VEGF and XBP1 mRNAs as well as the MVD were compared among patients with different clinicopathological features.Multivariate Cox regression analysis was done to evaluate the influencing factors of poor prognosis of glioma patients.Pearson correlation method was used to analyze the correlations between the relative expressions of VEGF and XBP1 mRNAs in glioma tissues and the MVD in glioma patients.According to the median relative expressions of VEGF and XBP1 mRNAs in glioma tissues and the median MVD,200 patients were divided into highly-expressed VEGF group(the relative expression of VEGF mRNA≥6.34,n=107),lowly-expressed VEGF group(the relative expression of VEGF mRNA<6.34,n=93),highly-expressed XBP1 group(the relative expression of XBP1 mRNA≥5.65,n=103),lowly-expressed XBP1 group(the relative expression of XBP1 mRNA<5.65,n=97),high MVD group(MVD≥33.85,n=101)and low MVD group(MVD<33.85,n=99).The patients were followed up for 3 years.Kaplan-Meier survival curves were plotted to compare the 3-year total survival rate between highly-and lowly-expressed VEGF and XBP1 groups and between high and low MVD groups.Results The relative expressions of VEGF and XBP1 mRNAs were glioma in cancer tissues(6.34±0.96,5.65±1.06)than those in paracancerous tissues(1.03±0.11,1.05±0.16)(t=77.715,P<0.001;t=60.684,P<0.001).The relative expressions of VEGF and XBP1 mRNAs in glioma tissues were higher in patients with pathological gradeⅢ-Ⅳ(6.66±0.87,5.93±0.89)and low differentiation(6.76±0.75,6.12±0.99)than those in patients with pathological gradeⅠ-Ⅱ(6.04±0.94,5.40±1.13)and moderately high differentiation(6.15±0.98,5.44±1.02)(t=4.767,P<0.001;t=3.666,P<0.001;t=4.738,P<0.001;t=4.399,P<0.001),and the MVDs were higher in patients aged≥50 years and pathological gradeⅢ-Ⅳ(35.45±7.99,35.77±7.27)than those in patients aged<50 years and pathological gradeⅠ-Ⅱ(32.08±7.80,32.04±8.37)(t=3.009,P=0.003;t=3.361,P=0.001).Pathological grade(HR=1.730,95%CI:1.427-3.154,P=0.008),relative expression of VEGF mRNA(HR=1.185,95%CI:1.027-1.514,P<0.001),relative expression of XBP1 mRNA(HR=1.178,95%CI:1.016-1.431,P=0.009)and MVD(HR=1.042,95%CI:1.009-1.226,P=0.023)were the influencing factors of poor prognosis of glioma patients.The relative expressions of VEGF and XBP1 mRNAs in glioma tissues were positively correlated with MVD(r=0.355,P<0.001;r=0.292,P<0.001).The 3-year total survival rates were lower in highly-expressed VEGF group,highly-expressed XBP1 group and high MVD group(13.08%,15.53%,15.84%)than those in lowly-expressed VEGF group,lowly-expressed XBP1 group and low MVD group(68.82%,63.92%,62.63%)(χ^(2)=62.518,P<0.001;χ^(2)=47.019,P<0.001;χ^(2)=39.034,P<0.001).Conclusions VEGF and XBP1 are highly expressed in glioma tissues.The expressions of VEGF and XBP1 are correlated with the pathological grade and differentiation degree,and positively correlated with MVD.The pathological gradeⅢ-Ⅳ,high expressions of VEGF and XBP1,and high MVD indicate a high risk of poor prognosis of glioma patients.