血清胰岛素样生长因子1与E-钙黏蛋白在胃癌患者中的表达及临床意义
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摘要
目的探讨胃癌患者血清胰岛素样生长因子1(insulin-like growth factor 1, IGF1)、E-钙黏蛋白(E-cadherin)水平变化及与预后的关系。方法胃癌患者158例为胃癌组,同期体检健康者158例为对照组,采用ELISA法检测2组血清IGF1、E-cadherin水平;分析血清IGF1、E-cadherin水平与胃癌临床病理特征的关系;ROC曲线分析血清IGF1、E-cadherin诊断胃癌的效能;随访5 a,比较不同血清IGF1、E-cadherin水平胃癌患者无进展生存期(progression-free survival, PFS)、总生存期(overall survival, OS),多因素Cox回归分析血清IGF1、E-cadherin对胃癌患者预后的影响。结果胃癌组血清IGF1[(102.83±10.22)μg/L]水平高于对照组[(46.48±8.94)μg/L],E-cadherin[(3.00±0.28)μg/L]水平低于对照组[(17.58±4.22)μg/L](P<0.05);胃癌组血清IGF1高表达者肿瘤低分化比率(64.79%)、浸润深度T_3～T_4期比率(71.83%)、有淋巴结转移比率(67.61%)、TNMⅢ～Ⅳ期比率(70.42%)高于IGF1低表达者(44.83%、50.57%、42.53%、44.83%)(P<0.05),E-cadherin高表达者浸润深度T_3～T_4期比率(46.75%)、有淋巴结转移比率(35.06%)、TNMⅢ～Ⅳ期比率(41.56%)低于E-cadherin低表达者(67.90%、71.60%、70.37%)(P<0.05);血清IGF1以56.0μg/L为最佳截断值,诊断胃癌的AUC为0.798(95%CI:0.786～0.904,P<0.001),灵敏度为82.5%,特异度为95.0%;血清E-cadherin以5.2μg/L为最佳截断值,诊断胃癌的AUC为0.838(95%CI:0.811～0.926,P<0.001),灵敏度为85.0%,特异度为90.0%;随访5 a,血清IGF1高表达者中位PFS(21.0个月)、中位OS(25.0个月)均较IGF1低表达者(44.0、48.0个月)短(P<0.05);血清E-cadherin高表达者中位PFS(29.5个月)、中位OS(39.5个月)较E-cadherin低表达者(17.5、23.0个月)长(P<0.05);多因素Cox回归分析结果显示,血清IGF1高表达(HR=3.011, 95%CI:1.649～4.307,P=0.020)、E-cadherin低表达(HR=2.691,95%CI:1.870～3.551,P=0.026)是胃癌患者预后的危险因素。结论胃癌患者血清IGF1表达升高,E-cadherin表达下调,IGF1高表达,E-cadherin低表达提示预后不良。
Objective To investigate the serum levels of insulin-like growth factor 1(IGF1) and E-cadherin in gastric cancer(GC) and their correlations with prognosis. Methods ELISA technique was used to detect the serum levels of IGF1 and E-cadherin in 158 GC patients(GC group) and 158 healthy volunteers(control group). The relationship of the levels of IGF1 and E-cadherin with the clinicopathological features was analyzed. The efficacies of serum IGF1 and E-cadherin on the diagnosis of gastric cancer were analyzed by ROC. The progression-free survival(PFS) and overall survival(OS) were compared in patients with different levels of serum IGF1 and E-cadherin in 5-year follow-up. The influences of serum IGF1 and E-cadherin on the prognosis of GC patients were analyzed by multivariate Cox proportional hazard analysis. Results The level of serum IGF1 was significantly higher and E-cadherin expression was significantly lower in GC group((102.83±10.22),(3.00±0.28) μg/L) than that in control group((46.48±8.94),(17.58±4.22) μg/L)(P<0.05). The proportions of poorly differentiated GC(64.79%), invasive depth stage T_3-T_4(71.83%), lymph node metastasis(67.61%) and TNM stage Ⅲ-Ⅳ(70.42%) in patients with highly expressed IGF1 were significantly higher than those in patients with lowly expressed IGF1 in GC group(44.83%, 50.57%, 42.53%, 44.83%)(P<0.05), and the proportions of invasive depth stage T_3-T_4(46.75%), lymph node metastasis(35.06%) and TNM stage Ⅲ-Ⅳ(41.56%) in patients with highly expressed E-cadherin were significantly lower than those in patients with lowly expressed E-cadherin(67.90%, 71.60%, 70.37%)(P<0.05). When the optimal cut-off of serum IGF1 was 56.0 μg/L, the AUC for the diagnosis of GC was 0.798(95%CI: 0.786-0.904, P<0.001), the sensitivity was 82.5% and the specificity was 95.0%;when the optimal cut-offof serum E-cadherin was 5.2μg/L,the AUCwas0.838(95%CI:0.811-0.926,P<0.001),the sensitivity was 85.0%,and specificity was 90.0%.The 5-year follow-up results showed that the median PFS and median OS were significantly shorter in patients with highly expressed IGF1(21.0,25.0 months)than those in patients with lowly expressed IGF1(44.0,48.0 months)(P<0.05),and were significantly longer in patients with highly expressed E-cadherin(29.5,39.5 months)than those in patients with lowly expressed E-cadherin(17.5,23.0 months)(P<0.05).Multivariate Cox proportional hazard analysis indicated that high expression of serum IGF1(HR=3.011,95%CI:1.649-4.307,P=0.020)and low expression of E-cadherin(HR=2.691,95%CI:1.870-3.551,P=0.026)were the risk factors for the prognosis in GC patients.Conclusion Serum IGF1 is highly expressed and E-cadherin is lowly expressed in GC patients,and lowly expressed E-cadherin indicates a poor prognosis.
Objective To investigate the serum levels of insulin-like growth factor 1(IGF1) and E-cadherin in gastric cancer(GC) and their correlations with prognosis. Methods ELISA technique was used to detect the serum levels of IGF1 and E-cadherin in 158 GC patients(GC group) and 158 healthy volunteers(control group). The relationship of the levels of IGF1 and E-cadherin with the clinicopathological features was analyzed. The efficacies of serum IGF1 and E-cadherin on the diagnosis of gastric cancer were analyzed by ROC. The progression-free survival(PFS) and overall survival(OS) were compared in patients with different levels of serum IGF1 and E-cadherin in 5-year follow-up. The influences of serum IGF1 and E-cadherin on the prognosis of GC patients were analyzed by multivariate Cox proportional hazard analysis. Results The level of serum IGF1 was significantly higher and E-cadherin expression was significantly lower in GC group((102.83±10.22),(3.00±0.28) μg/L) than that in control group((46.48±8.94),(17.58±4.22) μg/L)(P<0.05). The proportions of poorly differentiated GC(64.79%), invasive depth stage T_3-T_4(71.83%), lymph node metastasis(67.61%) and TNM stage Ⅲ-Ⅳ(70.42%) in patients with highly expressed IGF1 were significantly higher than those in patients with lowly expressed IGF1 in GC group(44.83%, 50.57%, 42.53%, 44.83%)(P<0.05), and the proportions of invasive depth stage T_3-T_4(46.75%), lymph node metastasis(35.06%) and TNM stage Ⅲ-Ⅳ(41.56%) in patients with highly expressed E-cadherin were significantly lower than those in patients with lowly expressed E-cadherin(67.90%, 71.60%, 70.37%)(P<0.05). When the optimal cut-off of serum IGF1 was 56.0 μg/L, the AUC for the diagnosis of GC was 0.798(95%CI: 0.786-0.904, P<0.001), the sensitivity was 82.5% and the specificity was 95.0%;when the optimal cut-offof serum E-cadherin was 5.2μg/L,the AUCwas0.838(95%CI:0.811-0.926,P<0.001),the sensitivity was 85.0%,and specificity was 90.0%.The 5-year follow-up results showed that the median PFS and median OS were significantly shorter in patients with highly expressed IGF1(21.0,25.0 months)than those in patients with lowly expressed IGF1(44.0,48.0 months)(P<0.05),and were significantly longer in patients with highly expressed E-cadherin(29.5,39.5 months)than those in patients with lowly expressed E-cadherin(17.5,23.0 months)(P<0.05).Multivariate Cox proportional hazard analysis indicated that high expression of serum IGF1(HR=3.011,95%CI:1.649-4.307,P=0.020)and low expression of E-cadherin(HR=2.691,95%CI:1.870-3.551,P=0.026)were the risk factors for the prognosis in GC patients.Conclusion Serum IGF1 is highly expressed and E-cadherin is lowly expressed in GC patients,and lowly expressed E-cadherin indicates a poor prognosis.
引文
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[12] 董海峰,郑英斌,庞志刚,等.E-钙黏蛋白与波形蛋白在胃癌中的表达及意义[J].中华实用诊断与治疗杂志,2018,32(6):580-582.
[13] KIM H J,LITZENBURGER B C,CUI X,et al.Constitutively active type 1 insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and Snail[J].Mol Cell Biol,2007,27(8):3165-3175.
[14] NAGLE A M,LEVINE K M,TASDEMIR N,et al.Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R/InsR inhibitors[J].Clin Cancer Res,2018,24(20):5165-5177.
[2] 李惠,孙怡,王双双,等.人表皮生长因子受体-2在胃癌活检标本和手术标本中表达及临床意义[J].中华实用诊断与治疗杂志,2016,30(2):153-156.
[3] 刘文佳,毛秋卉,张学俭,等.血清胃蛋白酶原和胃泌素-17筛选胃癌及癌前病变有效性[J].中华实用诊断与治疗杂志,2015,29(9):885-887.
[4] ZHANG M,LIU J,LI M,et al.Insulin-like growth factor 1/insulin-like growth factor 1 receptor signaling protects against cell apoptosis through the PI3K/AKT pathway in glioblastoma cells[J].Exp Ther Med,2018,16(2):1477-1482.
[5] LI Z,PAN W,SHEN Y,et al.IGF1/IGF1R and microRNA let-7e down-regulate each other and modulate proliferation and migration of colorectal cancer cells[J].Cell Cycle,2018,17(10):1212-1219.
[6] D'ALESSANDRO R,REFOLO M G,LIPPOLIS C,et al.Strong enhancement by IGF1-R antagonists of hepatocellular carcinoma cell migration inhibition by Sorafenib and/or vitamin K1[J].Cell Oncol (Dordr),2018,41(3):283-296.
[7] BATLLE E,SANCHO E,FRANCì C,et al.The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells[J].Nat Cell Biol,2000,2(2):84-89.
[8] 周文平,张琳琳.胰岛素样生长因子1与妊娠期高血压疾病产后遗留高血压相关性研究[J].中华实用诊断与治疗杂志,2016,30(6):594-595.
[9] JIANG H,WANG H,GE F,et al.The functional variant in the 3'UTR of IGF1 with the risk of gastric cancer in a Chinese population[J].Cell Physiol Biochem,2015,36(3):884-892.
[10] 王悦超,亓文骞,赵平.胰岛素样生长因子1受体在胰腺癌治疗中的机制及进展[J].临床肝胆病杂志,2017,33(4):790-794.
[11] XU L,ZHOU R,YUAN L,et al.IGF1/IGF1R/STAT3 signaling-inducible IFITM2 promotes gastric cancer growth and metastasis[J].Cancer Lett,2017,393:76-85.
[12] 董海峰,郑英斌,庞志刚,等.E-钙黏蛋白与波形蛋白在胃癌中的表达及意义[J].中华实用诊断与治疗杂志,2018,32(6):580-582.
[13] KIM H J,LITZENBURGER B C,CUI X,et al.Constitutively active type 1 insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and Snail[J].Mol Cell Biol,2007,27(8):3165-3175.
[14] NAGLE A M,LEVINE K M,TASDEMIR N,et al.Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R/InsR inhibitors[J].Clin Cancer Res,2018,24(20):5165-5177.