子宫内膜样腺癌中胰岛素样生长因子的基因表达与雌激素受体相关性探讨

目的胰岛素样生长因子(insulin-like growth factor,IGF)是多肽类生长激素中的一类,是细胞增生、分化过程中的促有丝分裂因子。有研究表明IGF在肿瘤细胞的增生分裂中起很重要的作用。文中探讨IGF-1和2及其受体基因在子宫内膜样腺癌中的表达模式,分析它们与雌激素受体(estrogen receptor,ER)亚型α、β间的关系以及临床病理意义。方法选取58例患者临床不同期的子宫内膜样腺癌组织标本(内膜癌组),同时选取癌旁组织31例(癌旁组)、正常内膜组织42例(对照组),采用TRizol一步法提取总RNA。TaqMan荧光实时定量PCR检测3组患者的IGF-1、IGF-2、IGF-1受体(insulin-likegrowth factor-1 receptor,IGF-1R)、IGF-2R、胰岛素样生长因子结合蛋白-3(insulin-like growth factor binding protein-3,IGFBP-3)、ERα、ERβ的mRNA表达,分析3组标本中的表达差异以及在内膜癌组织中的表达模式和相关关系。结果 IGF-1、IGF-1R、IGF-2、IGF-2R、IGFBP-3的mRNA表达量在内膜癌组中分别为1.19±0.79、6.23±3.98、2.44±2.32、4.32±2.98、14.47±12.31,在癌旁组中分别为2.66±1.73、35.34±22.02、8.59±7.13、0.39±0.36、8.28±4.57,均明显高于对照组中0.58±0.30、0.54±0.32、0.33±0.19、0.04±0.03、4.58±3.35,差异均有统计学意义(P<0.05)。癌旁组与内膜癌组比较,IGF-1、IGF-1R、IGF-2的mRNA量明显升高,而IGF-2R、IGFBP-3的mRNA则下降,差异均有统计学意义(P<0.05)。ERα、ERβ-mRNA表达水平在内膜癌组分别为10.67±7.63、31.44±25.22;对照组中分别为16.24±10.10、50.10±21.60(P<0.05),癌旁组中分别为45.54±33.58、529.62±296.70,较对照组及内膜癌组均显著增加,差异有统计学意义(P<0.05)。对照组中,ER与IGF之间无相关性。内膜癌组中ERα与IGF-1、IGF-2呈高度正相关,r分别为0.6439、0.5228;与IGF-2R呈轻度正相关,r为0.297 0;ERβ与IGF-1、IGF-2、IGF-2R呈轻度正相关,r分别为0.415 5、0.355 5、0.275 6;癌旁组中,ERα与IGF-1R、ERα与IGF-2、ERβ与IGF-2呈高度正相关,r分别为0.554 5、0.850 2、0.932 7,均有统计学意义(P<0.05),其他均显示无相关性。在内膜癌组织中IGF-1、IGF-2、IGF-2R、ERα、ERβ-mRNA表达量随着分期、分级以及浸润深度的增加呈下降趋势,而IGF-1R、IGFBP-3-mRNA表达量变化不明显;IGF-1、IGF-2、ERα、ERβ-mRNA与内膜癌分期、分级以及肌层浸润深度呈高度负相关,IGF-2R与分期、分级、浸润深度呈轻度负相关(P<0.05),IGF-1R和IGFBP-3与上述临床病理特征间相关性分析无统计学意义。结论癌旁组织和癌组织中IGF-1、IGF-2、IGF-1R的基因呈明显高表达,尤以癌旁组织中更明显;癌旁组织中ERα、ERβ的基因活性亦明显高于癌组织,癌组织中ERα、ERβ与IGF-1及IGF-2呈高度正相关,提示IGF-1和IGF-2可能激活ERα/ERβ,是正常内膜发生癌变的重要机制之一。IGF-1、IGF-2、IGF-2R、ERα、ERβ-mRNA高表达可能提示子宫内膜样腺癌预后良好。

Expressions of insulin-like growth factors in endometrioid adenocarcinoma and estrogen receptor subtypes

Objective The insulin-like growth factor(IGF) is one of the polypeptide growth hormones and plays an important role in many physiological activities,but its signal transduction disorder or abnormal expression can lead to carcinogen development.This study aimed to investigate the expressions of IGFs-mRNA in endometrioid adenocarcinoma and their relationship with estrogen receptor(ER) subtypes ERα and ERβ,as well as their clinicopathological implications.Methods We collected 58 specimens of endometrial adenocarcinoma(EA group),31 specimens of paracancerous tissue(PT group) and 42 specimens of normal endometrial tissue(NE group),extracted total RNA using One-Step Trizol,and detected the expressions of IGF-1,IGF-1R,IGF-2,IGF-2R,IGFBP-3,ERα and ERβ by TaqMan fluorescence real-time quantitative PCR.We analyzed the differential expressions in the three groups and the correlation among the expression patterns in endometrial carcinoma.Results The expression levels of IGF-1,IGF-1R,IGF-2,IGF-2R and IGFBP-3 were 1.19±0.79,6.23±3.98,2.44±2.32,4.32±2.98 and 14.47±12.31 in the EA group and 2.66±1.73,35.34±22.02,8.59±7.13,0.39±0.36 and 8.28±4.57 in the PT group,significantly higher than 0.58±0.30,0.54±0.32,0.33±0.19,0.04±0.03 and 4.58±3.35 in the NE group(P<0.05).The levels of IGF-1,IGF-1R and IGF-2-mRNA were remarkably increased,while the levels of IGF-2R and IGFBP-3-mRNA markedly decreased in the PT group compared with the EC group(P<0.05).The expressions ERα and ERβ mRNA were lower in the EC(10.67±7.63 and 31.44±25.22) than in the NE group(16.24±10.10 and 50.10±21.60)(P<0.05),but higher in the PT(45.54±33.58 and 529.62±296.7) than in the NE and EA groups(P<0.05).There was no correlation between the mRNA expressions of ER and IGF in the NE group.In the EA group,the expression of ERα mRNA was highly positively correlated with those of IGF-1 and IGF-2(r=0.643 9 and 0.522 8),and slightly with that of IGF-2R(r=0.297 0)(P<0.05).ERβ showed a slightly positive correlation with IGF-1,IGF-2 and IGF-2R(r=0.415 5,0.355 5 and 0.275 6).In the PT group,the expression of ERα mRNA was highly positively correlated with those of IGF-2 and IGF-1R(r=0.554 5 and 0.850 2,P<0.05),and so was ERβ with IGF-2(r=0.932 7,P<0.05).In the EA group,the mRNA expressions of IGF-1,IGF-2,IGF-2R,ERα and ERβ were negatively correlated with the stage,grade and depth of infiltration(P<0.05),while the expressions of IGF-1R and IGFBP-3 exhibited no correlation with them.Conclusion The activities of the IGF-1,IGF-2,IGF-1R,ERα and ERβ genes were markedly increased in paracancerous and cancerous tissues,and ERα and ERβ had a highly positive correlation with IGF-1 and IGF-2 in the cancerous tissue,which suggests that IGF-1 and IGF-2 could activate ERs in the endometrial carcinogen process.The overexpressions of IGF-1,IGF-2,IGF-2R,ERα and ERβ-mRNA might predict a good prognosis of endometrioid adenocarcinoma.