摘要
目的：分析探讨缺氧诱导因子-la(HIF-lα).血管通透因子(VEGF)和基质金属蛋白酶-9(MMP-9)在子宫内膜样腺癌中的表达及意义。探讨HIF-lα、VEGF和MMP-9蛋白表达之间的相互关系,以及在子宫内膜样腺癌发生、发展中的相互作用。
方法：选取60例子宫内膜样腺癌标本作为研究对象,30例良性子宫内膜组织标本(包括复杂性增生和不典型增生)作为对照。按照FIGO2000年子宫内膜癌手术一病理分期：Ⅰ期17例,Ⅱ期21例,Ⅲ期23例；按病理分化程度进行分级：高分化(G1)30例、中分化(G2)16例以及低分化(G3)14例。60例子宫内膜样腺癌标本年龄43～74岁,平均45.1岁,中位年龄47岁,良性子宫内膜对照组标本30例,26～73岁,平均47.4岁,中位年龄48岁；子宫内膜样腺癌标本来自妇科手术切除标本,子宫内膜增生标本则来自活组织检查标本和妇科因子宫肌瘤切除的子宫标本,所有病例均经过病理组织学确诊,并且经过两位高年资病理学医师阅片复诊。将子宫内膜样腺癌组织和良性子宫内膜分别构建组织芯片后,应用免疫组织化学PV-9000二步法检测HIF-lα、VEGF和MMP-9在子宫内膜样腺癌、良性子宫内膜对照组标本中的表达情况,应用SPSS(11.0FOR WINDOWS)软件统计学分析,采用X2检验,用Spearman相关性检验分析三个指标的关联性,分析不同组织类型、年龄、手术-病理分期、淋巴转移及病理分级等条件下三者的表达变化,分析三种基因蛋白在子宫内膜样腺癌组织中的表达与临床病理特征之间的关系。
结果：HIF-1α、VEGF和MMP-9在子宫内膜样腺癌中的阳性率高于良性子宫内膜对照组(P<0.05)。HIF-1α在对照组及子宫内膜癌中表达阳性率分别为43.30%(13／30)、73.30%(44／60),二者比较差异显著(X2=7.751,P＜0.01)。HIF-1α蛋白的阳性表达率Ⅰ期为35.29%(6／17),Ⅱ期为71.43%(15／21),Ⅲ期为78.26%(18／23),三者比较有显著性差异(X2=8.61,P＜0.05))；HIF-1α的表达与发病年龄无关(X2=0.057,P＞0.05)；HIF-1α在有淋巴结转移的子宫内膜样腺癌病例中的阳性率(85.70%)高于无淋巴结转移的癌组织病例(56.00%)(P＜0.05),与病理分级无关(X2=0.634,P＞0.05)。
VEGF在对照组及子宫内膜癌中表达阳性率分别为50.00%(15／30)和80.00%(48／60),二者比较差异有极显著性(X2=8.571,P＜0.05)；VEGF阳性表达率Ⅰ期为44.44%(8／18),Ⅱ期为80.00%(16／20),Ⅲ期为86.36%(19／22),三者比较有显著性差异(X2=9.59,P＜0.05))。VEGF的表达与发病年龄无关(X2=0.843,P＞0.05)；VEGF在有淋巴结转移的子宫内膜样腺癌病例中的阳性率(88.57%)高于无淋巴结转移的癌组织病例(52.00%)(P＜0.05),与病理分级无关。
MMP-9在对照组及子宫内膜癌表达阳性率分别为46.67%(14／30)、80.00%(48／60),二者比较差异显著(X2=10.369,P＜0.01)。MMP-9的阳性表达率Ⅰ期为41.18%(7／17),Ⅱ期为70.00%(14／20),Ⅲ期为82.61%(19／23),三者比较有显著性差异(X2=8.81,P＜0.05))；MMP-9的表达与发病患者年龄无关(X2=0.039,P＞0.05)；MMP-9在有淋巴结转移的子宫内膜样腺癌病例中的阳性率(91.43%)高于无淋巴结转移的癌组织病例(48.00%)(P<0.05),与病理分级无关。
子宫内膜癌组织中HIF-1α表达阳性组及阴性组中,VEGF表达的阳性率分别为86.36%(38／44)、62.50%(10／16),二者比较差异有显著性(r=0.264,P=0.042),VEGF的表达与HIF-1α正相关。子宫内膜癌组织中HIF-1α表达阳性、阴性组中,MMP-9表达的阳性率分别为88.64%(39／44)、56.25%(9／16),二者比较差异有显著性(r=0.358,P=0.005),MMP-9的表达与HIF-1α正相关。子宫内膜癌组织中VEGF表达阳性、阴性组中,MMP-9表达的阳性率分别为87.50%(42／48)、50.00%(6／12),二者比较差异有显著性(r=0.375,P=0.003),MMP-9的表达与HIF-la正相关。
结论：
1、HIF-1α、VEGF和MMP-9均在子宫内膜样腺癌中表达增高,提示可能参与了子宫内膜癌的发生、发展并相互作用。
2、HIF-1α、VEGF和MMP-9与子宫内膜样腺癌患者的病理分期呈正相关,提示与子宫内膜样腺癌的进展有关。
3、HIF-1α、VEGF和MMP-9在淋巴转移病例中表达升高,说明与子宫内膜样腺癌转移关系密切。
4、HIF-1α、VEGF和MMP-9与子宫内膜样腺癌病理分化程度无关,其高表达说明预后较差,有利于指导临床治疗。
5、子宫内膜癌组织中的、VEGF和MMP-9表达呈正相关性,HIF-1α、MMP-9通过上调VEGF的表达,促进肿瘤的血管生成,可将HIF-1α视为子宫内膜癌抗肿瘤新靶标。
Objective:To study the expressions of HIF-1α, VEGF and MMP-9in endometrioid adenocarcinoma and their clinicopathological relationship, and investigate the impact of HIF-1α、VEGF、and MMP-9, and the relation with HIF-1α、VEGF、and MMP-9protein over expression on the development and biological behavior of endometrial carcinoma.
Methods:Expressions of HIF-1α, VEGF and MMP-9in60cases of endometrioid adenocarcinoma and30cases of benign endometrial controls were detected, according to FIGO2000endometrial carcinoma operation-the pathological stage:Ⅰ (17cases), Ⅱ (21cases) and Ⅲ (23patients). Pathological grade is divided into well-differentiation (G1)30cases, moderate differentiation (G2)16cases and poor differentiation (G3)14cases. Endometrioid adenocarcinoma and benign endometrial tissue microarray were constructed. Application of SPSS (11FOR WINDOWS) software package was used for statistical analysis, and PV-9000two-step method for immunohistochemical staining. Using X2test, correlation analysis of three indexes by Spearman correlation test, the changes of expression of different tissue types, age, operation and pathological staging, lymph node metastasis were analized as well as the relationship between the expressions of three gene in endometrial adenocarcinoma and its clinicopathological features.
Results:The positive rate of HIF-1α, VEGF and MMP-9in endometrial adenocarcinoma was significantly higher than that in the benign endometrium (P<0.05). HIF-la in the control group and the endometrial carcinoma expression positive rates were43.30%,73.30%,(P<0.01). The positive expression of HIF-la protein rate in stage I35.29%(6/17), II71.43%(15/21) and Ⅲ78.26%(18/23), there was a significant difference among the three (P<0.05). The expression of HIF-la was not related age (P>0.05); the positive rate of lymph node metastasis in endometrial cancer cases (85.70%) was significantly higer than those without lymph node metastasis (56.00%)(P<0.05),and nothing to do with the pathological grade (P>0.05).
VEGF expression rates in the control group and the endometrial carcinoma were50.00%and80.00%, without significant difference (P<0.05); the positive expression rates of VEGF in stages were Ⅰ44.44%(8/18), Ⅱ80%(16/20) and Ⅲ86.36%(19/22), and there was a significant difference between the three (P<0.05). VEGF expression in the lymph node metastasis cases (88.57%) was higher than those of without lymph node metastasis cases (52.00%) P<0.05, and no difrencese were found in age of onset (P>0.05) and pathological grade groups.
MMP-9expression was significantly higher in the endometrium cancer casese (80.00%) than that of benign group,(46.67%, P<0.01) as well as in lymph node metastasis (91.43%) than that of none lymph node metastasis casese (48.00%P<0.05), and there was difference of MMP-9expression in stages Ⅰ (41.18%),11(70.00%),Ⅲ (82.61%),(P<0.05). The expressions of MMP-9were not related to age of onset (P>0.05) and pathological grading.
VEGF expression rates of endometrial carcinoma were86.36%and62.50%in HIF-la positive group and negative group respectively, there was significant corelationship between VEGF and HIF-la (r=0.264, P=0.042). Samiliar results were obertaned in MMP-9expressions (88.64%,56.25%in HIF-la positive and negative cases respectively) and significant corelationship was found as well (r=0.358, P=0.005). The positive rates of MMP-9expressions were87.50%, and50.00%in VEGF positive and negative groups respectively, and there was a significant correlation (r=0.375, P=0.003) similar above.
Conclusions:
1. HIF-la, VEGF and MMP-9were over expressed in endometrial adenocarcinoma, suggesting that may be involved in the occurrence and development of endometrial carcinoma.
2. Positive expressions of HIF-1α, VEGF and MMP-9in staging operation-pathology, associated with progress in endometrial adenocarcinoma.
3. HIF-la, VEGF and MMP-9were positively correlated with lymph node metastasis.
4. HIF-la, VEGF and MMP-9expressions were not related to pathologic grades which indicate poor prognosis with higher expressions.
5.The expression of endometrial carcinoma HIF-la, VEGF and MMP-9were positively correlated, HIF-1α, MMP-9may up-regulate the expression of VEGF, and promote tumor angiogenesis, in endometrial cancer has an important role in the development, HIF-la may be regarded as a possible tumor marker in invasion and metastasis of endometrial carcinoma and a new target for tumor therapy.
引文
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