HIF-1a在子宫内膜腺癌中表达的意义
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摘要
【目的】
探讨HIF-1α在子宫内膜腺癌组织中的表达状态以及与肿瘤血管生成、临床病理因素、预后之间的关系,并揭示子宫内膜腺癌中HIF-1α与ERα之间的关系。
【材料与方法】
免疫组化法检测56例子宫内膜腺癌、18例子宫内膜不典型增生、20例正常子宫内膜组织中HIF-1α、VEGF、ERα蛋白的表达,及CD105标记血管内皮细胞的微血管密度,对全组病人进行随访,获得随访资料进行生存分析。
【结果】
1.在正常子宫内膜组织、子宫内膜不典型增生及子宫内膜癌中HIF-1α蛋白表达阳性率分别为45.0%、27.8%、60.7%。三者之间差异有显著性意义(P＜0.05)。HIF-1α与临床病理特征无相关性,但HIF-1α阳性患者的5年生存率低于阴性患者(P＜0.05)。
2.ERa在正常子宫内膜组织、子宫内膜不典型增生及子宫内膜癌中的阳性表达率呈下降趋势,分别为100%、77.7%和60.7%。三者之间差异有显著性意义(P＜0.05)。ERa表达与有否绝经、手术—病理分期、组织学分级及盆腔淋巴结转移无关(P均＞0.05)。但浸润肌层突破1/2者ERa阳性表达率显著低于浸润肌层深度在1/2以内者(P＜0.05)。ERa阴性与阳性两组生存时间差异比较无显著性意义(P＞0.05)。
3.VEGF在正常子宫内膜、子宫内膜不典型增生及子宫内膜癌组织中阳性表达率分别为60.0%、72.2%、89.3%,三者之间差异有显著性意义(P＜0.05)。VEGF在子宫内膜癌中明显高于正常子宫内膜组织及子宫内膜不典型增生(P＜0.05),VEGF蛋白与临床病理特征及生存时间均无关(P＞0.05)。
4.以CD105作为血管标记物计算微血管密度(MVD),在正常子宫内膜、子宫内膜不典型增生及子宫内膜癌组织中分别为21.6±11.5、27.9±13.7、47.7±12.8。统计学分析三者差异有显著性意义(P＜0.05)。MVD在子宫内膜癌中明显高于正常子宫内膜组织及子宫内膜不典型增生(P＜0.05),CD105-MVD与绝经与否、组织学分级及局部淋巴结转移无关(P＞0.05),与浸润肌层深度、手术-病理分期有关(P＜0.05)。随着分期及浸润肌层深度增加,CD105-MVD越大。高CD105-MVD患者的5年生存率低于低CD105-MVD患者,但两组比较差异无显著性意义(P=0.0767)。
5.相关分析显示,HIF-1α在子宫内膜癌组表达与ERa呈正相关(r=0.265P=0.049),与CD105-MVD呈正相关(r=0.282 P=0.035),与VEGF呈正相关(r=0.355 P=0.007)。
【结论】
1.HIF-1α在子宫内膜腺癌中存在着过表达,并且与肿瘤血管生成密切相关,与不良的预后有关。HIF-1α通过促进肿瘤血管生成,在子宫内膜癌的发生发展中起着重要作用,可能作为肿瘤生物学行为的标志,并成为抗肿瘤治疗的新靶向。
2.探讨子宫内膜癌中HIF-1α与ERa表达的相关性为研究雌激素在子宫内膜癌发生和发展的机制提供新的线索,阻止HIF-1a可能成为治疗雌激素依赖性疾病的方法,针对HIF-1a与ERa联合治疗则可能更有效。
【Objective】
To study the expression of HIF-1 a in endometrial adenocarcinoma and their relationship with tumor angiogenesis,several histopathologic parameters and patient prognosis.In addition,the relationship between HIF-1αand ERαis studied.
【Methods】
HIF-1α、VEGF、ERαproteins and CD105-MCV were studied immunohistochemically in a group of 56 patients with endometrial adenocarcinoma, 20 patients with normal endometria and 18 patients with atypia hyperplasia.Survival analysis was also studied.
【Results】
1.In 60.7%of endometrial adenocarcinoma、27.8%of atypia hyperplasia and 45.0%normal endometria,expression of HIF-1a was observed.There was a significant difference between them(P＜0.05).HIF-1a overexpression showed no significant correlation with histopathologic parameters but has an impact on survival of cancer patients(P＜0.05).
2.ERa expression was detected in 60.7%of endometrial adenocarcinoma and 77.7%、100%in atypia hyperplasia and normal endometria,respectively.There was a significant difference between them(P＜0.05).High ERa protein expression was associated significantly with the less depth of myometrial invasion(P＜0.05),but it has no impact on survival of cancer patients(P＞0.05).
3.The VEGF positive expression rate(89.3%)in endometrial adenocarcinoma was significantly higher than that in atypia hyperplasia(72.2%)and normal endometria(60.0%)(P＜0.05).Increased VEGF expression has no association with clinic pathological parameters and survival time(P＞0.05).
4.The CD 105-MVD in normal endometria、atypia hyperplasia and endometrial adenocarcinoma was 21.6±11.5、27.9±13.7 and 47.7±12.8 respectively.The CD 105-MVD in endometrial adenocarcinoma was significantly higher than that in atypia hyperplasia and normal endometrium(P＜0.05)and was significantly correlated with the clinical stage、depth of myometrial invasion.There was a marginal association of high CD105-MVD and a poor prognosis(P=0.0767).
5.In the cases of endometrial adenocarcinoma,there was a positive correlation between expression of HIF-1a and ERa(r=0.265,P=0.049),HIF-1a and VEGF(r= 0.355 P=0.007),HIF-1a and CD105-MVD(r=0.282 P=0.035).
【Conclusions】
1.The up-regulation of HIF-1a is a common event in endometrial adenocarcinoma.HIF-1 a expression is related to increased angiogenesis,and to an unfavorable prognosis in endometrial adenocarcinoma.HIF-1αis considered a likely target for the treatment of endometrial adenocarcinoma.
2.The correlation of HIF-1a and ERa protein expression provides a new clue to the mechanism and treatment of ERαon endometrial adenocarcinoma.Inhibiting HIF-1αaction could be an approach for the treatment of E2-dependent diseases of the uterus.Combinatorial treatments that target both ERαand HIF-1αmight be especially effective for the treatment of endometrial adenocarcinoma.
探讨HIF-1α在子宫内膜腺癌组织中的表达状态以及与肿瘤血管生成、临床病理因素、预后之间的关系,并揭示子宫内膜腺癌中HIF-1α与ERα之间的关系。
【材料与方法】
免疫组化法检测56例子宫内膜腺癌、18例子宫内膜不典型增生、20例正常子宫内膜组织中HIF-1α、VEGF、ERα蛋白的表达,及CD105标记血管内皮细胞的微血管密度,对全组病人进行随访,获得随访资料进行生存分析。
【结果】
1.在正常子宫内膜组织、子宫内膜不典型增生及子宫内膜癌中HIF-1α蛋白表达阳性率分别为45.0%、27.8%、60.7%。三者之间差异有显著性意义(P＜0.05)。HIF-1α与临床病理特征无相关性,但HIF-1α阳性患者的5年生存率低于阴性患者(P＜0.05)。
2.ERa在正常子宫内膜组织、子宫内膜不典型增生及子宫内膜癌中的阳性表达率呈下降趋势,分别为100%、77.7%和60.7%。三者之间差异有显著性意义(P＜0.05)。ERa表达与有否绝经、手术—病理分期、组织学分级及盆腔淋巴结转移无关(P均＞0.05)。但浸润肌层突破1/2者ERa阳性表达率显著低于浸润肌层深度在1/2以内者(P＜0.05)。ERa阴性与阳性两组生存时间差异比较无显著性意义(P＞0.05)。
3.VEGF在正常子宫内膜、子宫内膜不典型增生及子宫内膜癌组织中阳性表达率分别为60.0%、72.2%、89.3%,三者之间差异有显著性意义(P＜0.05)。VEGF在子宫内膜癌中明显高于正常子宫内膜组织及子宫内膜不典型增生(P＜0.05),VEGF蛋白与临床病理特征及生存时间均无关(P＞0.05)。
4.以CD105作为血管标记物计算微血管密度(MVD),在正常子宫内膜、子宫内膜不典型增生及子宫内膜癌组织中分别为21.6±11.5、27.9±13.7、47.7±12.8。统计学分析三者差异有显著性意义(P＜0.05)。MVD在子宫内膜癌中明显高于正常子宫内膜组织及子宫内膜不典型增生(P＜0.05),CD105-MVD与绝经与否、组织学分级及局部淋巴结转移无关(P＞0.05),与浸润肌层深度、手术-病理分期有关(P＜0.05)。随着分期及浸润肌层深度增加,CD105-MVD越大。高CD105-MVD患者的5年生存率低于低CD105-MVD患者,但两组比较差异无显著性意义(P=0.0767)。
5.相关分析显示,HIF-1α在子宫内膜癌组表达与ERa呈正相关(r=0.265P=0.049),与CD105-MVD呈正相关(r=0.282 P=0.035),与VEGF呈正相关(r=0.355 P=0.007)。
【结论】
1.HIF-1α在子宫内膜腺癌中存在着过表达,并且与肿瘤血管生成密切相关,与不良的预后有关。HIF-1α通过促进肿瘤血管生成,在子宫内膜癌的发生发展中起着重要作用,可能作为肿瘤生物学行为的标志,并成为抗肿瘤治疗的新靶向。
2.探讨子宫内膜癌中HIF-1α与ERa表达的相关性为研究雌激素在子宫内膜癌发生和发展的机制提供新的线索,阻止HIF-1a可能成为治疗雌激素依赖性疾病的方法,针对HIF-1a与ERa联合治疗则可能更有效。
【Objective】
To study the expression of HIF-1 a in endometrial adenocarcinoma and their relationship with tumor angiogenesis,several histopathologic parameters and patient prognosis.In addition,the relationship between HIF-1αand ERαis studied.
【Methods】
HIF-1α、VEGF、ERαproteins and CD105-MCV were studied immunohistochemically in a group of 56 patients with endometrial adenocarcinoma, 20 patients with normal endometria and 18 patients with atypia hyperplasia.Survival analysis was also studied.
【Results】
1.In 60.7%of endometrial adenocarcinoma、27.8%of atypia hyperplasia and 45.0%normal endometria,expression of HIF-1a was observed.There was a significant difference between them(P＜0.05).HIF-1a overexpression showed no significant correlation with histopathologic parameters but has an impact on survival of cancer patients(P＜0.05).
2.ERa expression was detected in 60.7%of endometrial adenocarcinoma and 77.7%、100%in atypia hyperplasia and normal endometria,respectively.There was a significant difference between them(P＜0.05).High ERa protein expression was associated significantly with the less depth of myometrial invasion(P＜0.05),but it has no impact on survival of cancer patients(P＞0.05).
3.The VEGF positive expression rate(89.3%)in endometrial adenocarcinoma was significantly higher than that in atypia hyperplasia(72.2%)and normal endometria(60.0%)(P＜0.05).Increased VEGF expression has no association with clinic pathological parameters and survival time(P＞0.05).
4.The CD 105-MVD in normal endometria、atypia hyperplasia and endometrial adenocarcinoma was 21.6±11.5、27.9±13.7 and 47.7±12.8 respectively.The CD 105-MVD in endometrial adenocarcinoma was significantly higher than that in atypia hyperplasia and normal endometrium(P＜0.05)and was significantly correlated with the clinical stage、depth of myometrial invasion.There was a marginal association of high CD105-MVD and a poor prognosis(P=0.0767).
5.In the cases of endometrial adenocarcinoma,there was a positive correlation between expression of HIF-1a and ERa(r=0.265,P=0.049),HIF-1a and VEGF(r= 0.355 P=0.007),HIF-1a and CD105-MVD(r=0.282 P=0.035).
【Conclusions】
1.The up-regulation of HIF-1a is a common event in endometrial adenocarcinoma.HIF-1 a expression is related to increased angiogenesis,and to an unfavorable prognosis in endometrial adenocarcinoma.HIF-1αis considered a likely target for the treatment of endometrial adenocarcinoma.
2.The correlation of HIF-1a and ERa protein expression provides a new clue to the mechanism and treatment of ERαon endometrial adenocarcinoma.Inhibiting HIF-1αaction could be an approach for the treatment of E2-dependent diseases of the uterus.Combinatorial treatments that target both ERαand HIF-1αmight be especially effective for the treatment of endometrial adenocarcinoma.
引文
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