CD44v6与人乳头瘤病毒在宫颈鳞癌及癌前病变中的相关性研究

目的:观察CD44v6与人乳头瘤病毒(HPV)在宫颈鳞癌及癌前病变中的相关性,以探讨两者联合检测在宫颈癌早期诊断中的意义。方法:采用免疫组化(SP)法检测宫颈鳞癌、宫颈上皮内瘤变(CIN)Ⅰ、CINⅡ、CINⅢ及正常宫颈组织各20例石蜡标本中CD44v6的表达,同时用荧光定量聚合酶链反应(FQ-PCR)法检测上述组织中HPV-DNA的相对含量,将两者检测的结果进行统计学分析并研究其相关性。结果:CD44v6在对照组、CINⅠ组、CINⅡ组、CINⅢ组及宫颈鳞癌组中细胞表达的阳性率逐渐升高,5组比较差异有统计学意义(P<0.05);HPV感染率也逐渐升高,5组比较差异有统计学意义(P<0.05);CD44v6与HPV感染呈正相关(rs=0.341,P=0.01)。结论 :CD44v6的异常表达和HPV感染与宫颈癌的发生、发展关系密切,两者联合检测对宫颈癌的早期诊断有一定的临床意义。     

整合素连接激酶在宫颈上皮内瘤变及宫颈癌组织中的表达及临床意义

目的 探讨整合素连接激酶(ILK)在宫颈上皮内瘤变(CIN)及宫颈癌组织中的表达及临床意义.方法 2000年1月至2007年12月在沧州中西医结合医院采用免疫组化技术(S-P法)检测ILK在99例宫颈CIN和宫颈癌中的表达.结果 ILK在正常宫颈黏膜上皮、CIN I～Ⅱ级、CINⅢ级、浸润癌表达的阳性率分别为26.7%、72.O%、80.0%、97.9%.各级CIN与浸润癌相比ILK的表达率差异有统计学意义(P<0.05).ILK表达率与临床分期及病理分级有关(P<0.05).结论 ILK可作为反映宫颈上皮增生病变程度及生物学行为的指标,对宫颈非浸润性病变与浸润性病变的诊断及鉴别有参考价值.     

宫颈鳞癌中膜突蛋白及CD105的表达及其临床意义

目的:研究膜突蛋白(Moesin)及CD105在各级宫颈病变中的表达水平,探讨其与宫颈鳞癌的发展及浸润的关系。方法:采用免疫组化SP法检测31例正常宫颈组织(NCE)、48例宫颈上皮内瘤样变(CIN)及66例宫颈鳞癌组织(SCC)中Moesin及CD105的表达。结果:从NCE到CIN到SCC组,Moesin的表达水平显著升高。在CIN组Moesin的表达随病变程度加重而升高;SCC组中与FIGO分期、浸润深度、盆腔淋巴转移有关,与组织分化程度及年龄无关。从NCE到CIN到SCC组,CD105表达的微血管密度(MVD)值显著升高,在SCC组中与淋巴转移及浸润深度有关,且与Moesin蛋白具有较高关联性。结论:Moesin蛋白及CD105可能在宫颈鳞癌的发展及转移过程中起重要作用,二者结合可能成为判断宫颈病变生物学行为的重要指标。     

Survivin、CD44v6、MMP-2在宫颈癌组织中的表达与侵袭、转移的关系

目的探讨Survivin基因、细胞粘附分子CD44v6、基质金属蛋白酶-2(MMP-2)蛋白在人宫颈癌中的表达水平与宫颈癌组织侵袭、转移能力的关系.方法采用免疫组织化学法和图像分析系统方法检测Survivin、CD44v6、MMP-2在10例正常宫颈、10例宫颈原位癌、40例宫颈鳞癌、11例宫颈腺癌组织中的表达,分析表达结果与临床病理特征的关系.结果从正常宫颈上皮到原位癌再到浸润癌,Survivin、CD44v6、MMP-2阳性表达量显著升高(P＜0.05).有盆腔淋巴结转移、脉管或(和)间质侵袭、年龄小于35岁患者的Survivin、CD44v6、MMP-2阳性表达量较其对应组增多(P＜0.05);腺癌Survivin阳性表达量高于鳞癌,而CD44v6、MMP-2的表达在鳞癌中高于腺癌(P＜0.05).结论Survivin蛋白异常表达在宫颈癌的恶化、侵袭、转移中起重要作用,它与宫颈癌组织细胞生物学特点密切相关,并与CD44v6、MMP-2共同在宫颈癌组织中的阳性表达可能在宫颈癌发生发展、组织侵袭、转移中起重要作用.     

CD1a和E-cadherin在宫颈上皮内瘤变中的表达

目的:探讨CD1a和E-cadherin与宫颈癌发生发展的关系及作为早期癌变生物学指标的可能性。方法:采用免疫组化SP法检测CD1a和E-cadherin在同期56例宫颈上皮内瘤变、56例宫颈鳞癌和15例正常宫颈组织中的分布及表达。结果:(1)CD1a+朗格汉斯细胞在正常宫颈、CIN和宫颈癌各组中数量逐渐减少,两两比较有显著差异(P0.01);CIN中该细胞数量随病变严重程度减少,CINⅠ和CINⅡ、CINⅠ和CINⅢ组之间两两比较有显著差异(P0.05),而CINⅡ与CINⅢ组间无显著差异(P0.05);(2)E-cadher-in在正常宫颈、CIN和宫颈癌各组中的阳性表达率及强度逐渐下降,两两比较有显著差异(P0.05);在CIN中阳性表达率及表达强度随病变严重程度呈下降趋势,CINⅠ和CINⅡ、CINⅠ和CINⅢ之间两两比较有显著差异(P0.05),而CINⅡ和CINⅢ之间无显著差异(P0.05);(3)宫颈组织中CD1a+朗格汉斯细胞的细胞数与E-cadherin的阳性表达率及强度呈正相关(r=0.912,P0.05)。结论:CD1a+朗格汉斯细胞与E-cadherin可能在宫颈癌的发生、发展过程中起重要作用。     

高迁移率蛋白A2在不同宫颈病变中的表达及意义

目的探讨高迁移率蛋白A2(HMGA2)在不同宫颈病变组织中的表达及其临床意义,了解其与宫颈人乳头瘤病毒(HPV)感染的关系。方法免疫组织化学法检测无锡市第三人民医院2005至2007年30例正常宫颈组织、19例低级别上皮内瘤样病变宫颈组织、16例高级别上皮内瘤样病变宫颈组织、13例宫颈鳞癌组织中HMGA2蛋白的表达,原位杂交检测各组织中HPV感染的情况,分析HMGA2蛋白表达与HPV感染在宫颈病变组织中的相关性。结果正常宫颈组织、CINⅠ级、CINⅡ~Ⅲ级和宫颈浸润性鳞癌组织中,HMGA2蛋白的阳性表达率分别为26.67%、21.05%、68.75%和76.92%。CINI与正常宫颈组织阳性表达率比较,差异无统计学意义;CINⅡ~Ⅲ级、宫颈浸润性鳞癌组织与正常宫颈组织阳性表达率比较,差异有统计学意义(P=0.011,P=0.006)。宫颈高级别上皮内瘤样病变和宫颈癌组织具有较高的HPV感染率,HPV感染与否和HMGA2的表达两者之间未发现统计学相关性。结论HMGA2高表达于高级别宫颈上皮内瘤样病变组织和宫颈癌组织,这可能是宫颈病变的一个早期事件。HMGA2的表达与宫颈HPV感染两者没有相关性,HMGA2可能是...     

ABCG2与CD133在宫颈癌的表达及意义

目的:探讨ABCG2及CD133蛋白在宫颈癌的表达及临床意义。方法:用免疫组化SP法检测92例宫颈癌、40例宫颈上皮内瘤变(CIN)和30例正常宫颈组织中AB-CG2及CD133蛋白的表达。结果:ABCG2在宫颈癌、CIN和正常宫颈组织的阳性表达率分别为69.6%、42.5%、23.3%,CD133为57.6%、37.5%、23.3%,两者在宫颈癌的表达均高于CIN及正常组织,差异均有统计学意义(P0.05);两者表达与宫颈癌患者年龄、肿瘤大小、临床分期无相关性(P0.05),而在不同分化组间表达的差异有统计学意义(P0.05)。结论:ABCG2和CD133蛋白异常表达与宫颈癌的发生、发展有关,二者联合检测可作为评估宫颈癌恶性程度、指导治疗的重要参考指标。     

CD13在宫颈癌中的表达及意义

目的:探讨CD13在宫颈癌患者中的表达及临床意义。方法:用免疫组化SP法检测60例宫颈癌、60例宫颈上皮内瘤变(CIN)和30例正常宫颈组织中的CD13表达情况。结果:CD13在宫颈癌、CIN和正常宫颈组织中的阳性表达率分别是81.7%、31.7%、20.0%,CD13在宫颈癌中的表达均显著高于CIN及正常组织(P均<0.05)。CD13表达与宫颈癌患者年龄无相关性(P>0.05),而与淋巴转移、临床分期以及分化程度有相关性(P<0.05)。结论:CD13在宫颈癌的异常表达与宫颈癌的发生、发展有关,可作为评估宫颈癌的恶性程度、指导治疗、评价预后的重要参考指标。     

核因子κB、肿瘤坏死因子α在宫颈癌变过程中的表达及临床意义

目的:探讨核因子κB(NF-κB)p65、肿瘤坏死因子α(TNFα)在宫颈癌变过程中的表达及临床意义。方法:采用免疫组化SABC法分别检测20例正常宫颈,11例CINⅠ,10例CINⅡ～Ⅲ和69例宫颈鳞癌中NF-κBp65亚基、TNFα的表达,探讨两者的表达水平与宫颈鳞癌临床病理特征的关系。结果:NF-κBp65在宫颈鳞癌中的表达明显高于正常宫颈、CINⅠ、CINⅡ～Ⅲ组(P<0.01),以细胞核染色为活性染色。TNFα在宫颈鳞癌中的表达明显高于正常宫颈、CINⅠ、CINⅡ～Ⅲ组(P<0.01),以细胞浆染色为主。NF-κBp65和TNFα在宫颈鳞癌组织中的表达水平正相关(rs=0.6317,P<0.01)。NF-κBp65、TNFα在低分化、瘤体直径≥4cm、浸润深度>1/2和淋巴结转移癌组织中的阳性表达均高于中-高分化、瘤体直径<4cm、浸润深度≤1/2、无淋巴结转移的癌组织(P<0.05)。TNFα在癌组织肿瘤细胞和间质中的表达率分别为72.46%、18.84%(P<0.01)。结论:NF-κB、TNFα的过度激活在宫颈鳞癌的发生、发展中可能起重要作用,且宫颈鳞癌细胞自分泌TNFα可能是NF-κB激活的重要原因。     

吲哚胺2,3-二氧酶在CIN及宫颈鳞癌中的表达及其意义

目的:探讨吲哚胺2,3-二氧酶(indoleamine 2,3-dioxygenase,IDO)在宫颈上皮内瘤变(CIN)及宫颈鳞癌中的表达及意义.方法:选择经病理确诊为CIN Ⅰ～CIN Ⅲ和宫颈鳞癌患者的石蜡标本116例,以同时期因子宫肌瘤行全子宫切除患者的正常宫颈组织石蜡标本20例作为对照,采用免疫组化方法检测宫颈CIN及宫颈鳞癌中IDO表达情况.结果:正常宫颈组织和CIN Ⅰ,CIN Ⅱ～CIN Ⅲ,宫颈鳞癌ⅠA期～ⅠB期,ⅡA期～ⅣB期4组之间IDO阳性表达强度差异有高度统计学意义(P＜0.01).在宫颈鳞癌Ⅰ～Ⅳ期IDO总阳性表达率为100%,ⅠA期～ⅠB期IDO总阳性表达率显著高于CIN Ⅱ和CIN Ⅲ(P＜0.01),ⅡA～ⅣB期IDO阳性表达强度显著高于ⅠA期～ⅠB期(P＜0.01).IDO表达与宫颈鳞癌进展有关(OR=0.779,JP＜0.01);在宫颈鳞癌淋巴转移阳性组IDO阳性表达强度显著高于淋巴转移阴性组(P＜0.01);IDO表达与肿瘤分化程度无相关性(P＞0.05).结论:从CIN Ⅱ开始,肿瘤组织已逐步建立起有利于肿瘤发展的免疫逃逸机制.IDO的表达与疾病进展有关而与肿瘤组织分化程度无关,IDO可能成为宫颈鳞癌预后的预测因子及治疗靶点.     

Expression of CD44 in uterine cervical squamous neoplasia: a predictor of microinvasion?

OBJECTIVE: CD44, an integral membrane glycoprotein, may have an important role in early tumorigenesis, specifically, facilitating early tumor progression. Reports of the expression of CD44 in early uterine cervical squamous carcinogenesis are conflicting. We examined the expression of CD44 in microinvasive carcinoma of the cervix (MIC), as yet unreported, and compared it to that in cervical intraepithelial neoplasia (CIN) 1 and CIN 3 to further elucidate its role in early squamous carcinogenesis. METHODS: Seventeen cases of CIN 1, 24 cases of CIN 3, and 20 cases of MIC were stained with antibodies to CD44s, CD44v5, and CD44v6. Only membranous staining was considered positive. RESULTS: Positive membranous staining (>50% cells) was observed in 97% of cases of CIN 1 using all three antibodies. In CIN 3, positive staining was seen more often with CD44v6 (18/24) and CD44v5 (19/24) than with CD44s (6/24). Expression of CD44v6 was retained more often in MIC (16/20) compared with CD44s (3/20) and CD44v5 (9/20). Those cases of CIN 3 and MIC that failed to meet our criteria for positive staining showed either heterogeneous or absent staining. CONCLUSION: There is a qualitative and quantitative reduction in expression of CD44 in MIC and CIN 3 compared with CIN 1. Down-regulation of CD44 variants may occur later in neoplastic progression than CD44s. This pattern may reflect their important biological function in early progression by cervical cancer cells. Patchy and heterogeneous staining in more advanced lesions limits the usefulness of CD44 and its variants in the assessment of microinvasion.     

CD44 is a marker of endocervical neoplasia.

The expression of CD44s, CD44v4, CD44v5, CD44v7-8, and CD44v10 was investigated immunohistochemically in a variety of neoplastic cervical lesions. Normal endocervical columnar cells exhibited no reactivity for any of the antibodies, whereas the subcolumnar reserve cells were strongly positive for CD44s, CD44v5, and CD44v7-8. In some cases, positive cells were identified in the stroma surrounding the endocervical glands and adjacent to reserve cells. Cervical glandular intraepithelial neoplasia and adenocarcinoma showed consistent immunoreactivity for CD44v5. There was no significant change in CD44 immunoreactivity in squamous cell carcinoma compared with normal epithelia and cervical intraepithelial neoplasia. These findings lend support to the origin of carcinoma of the cervix from a common progenitor reserve cell and suggest the origin of reserve cells from the stroma. CD44v5 may be useful as a diagnostic marker of endocervical neoplasia and could provide a target for therapeutic approaches directed against specific epitopes.     

CD44 splice variant expression in normal and malignant uterine cervical epithelium

Uhl-Steidl M, Huy VQ, Müller-Holzner E, Ruth N, Zeimet AG, Stauder R, Daxenbichler G, Marth C. CD44 splice variant in normal and malignant uterine cervical epithelium. Int J Gynecol Cancer 1998; 8 : 460–466.
CD44 expression was investigated immunohistochemically on paraffin sections obtained from 88 uterine cervical cancers and 31 normal cervices, using monoclonal antibodies against CD44 variant epitopes v4, v5, v6, v7/8, v9 and the standard form of the CD44 protein. Normal epithelium showed expression of all CD44 splice variants, at least in traces, and it was located predominantly in basal and parabasal cells. In cervical carcinomas CD44 expression was widely heterogeneous. CD44 variant v9 staining was moderate or strong in 86% of the tumors, and it was significantly correlated with CD44 v6 staining. Also a significant correlation between expression of CD44 v4 and v6 occurred. Highly significant correlations between CD44 expression of variants v4 and v6 and tumor stage as well as patients age were found. In addition, these variants were more frequently expressed in squamous cell carcinomas than in adenocarcinomas. However, in contrast to the recently reported data, we were not able to confirm the hypothesis that CD44 v6 represents a prognostic indicator in cervical cancer. In FIGO stages III and IV, patients with CD44 variant v4 positive tumors had a significantly longer disease-free and overall survival than patients with CD44 variant v4 negative tumors. In conclusion, our data indicate that CD44 v6 tissue expression cannot be considered as a prognostic factor in cervical cancer. Regarding the unexpected outcome of patients with CD44 v4 positive tumors, further investigations are needed to elucidate the exact clinical value of this variant isoform.     

Prognostic value of CD44 expression in invasive squamous cell carcinoma of the vulva.

OBJECTIVE: CD44 is a cell adhesion molecule that binds extracellular matrix. CD44 isoforms arising from alternative mRNA splicing are implicated in tumor metastases. The aim of our study is to investigate the expression of CD44 splice variants and its correlation to lymph node metastases and disease-free survival in squamous cell carcinoma (SCC) of the vulva. METHODS: Thirty-five cases of SCC of the vulva were evaluated for CD44 splice variants -3v, -4v, -5v, and -7v expression by immunocytochemistry. When available one nonmetastatic lymph node (LN) was also studied. In cases with LN metastases, the metastatic LN as well as a nonmetastatic LN from the same patient were evaluated. RESULTS: All CD44 variants studied were expressed in all epithelium: normal, dysplastic, and SCC. CD44 variants showed decreased immunostaining in the tumor cells when compared to normal epithelium. Furthermore, intensity of expression of the CD44 isoforms changed within the tissue containing invasive cancer. Interestingly, CD44-4v expression was downregulated in the most differentiated cells within the carcinoma, mainly in patients who had disease recurrence or died of disease (P = 0.004). Confirming prior publications, CD44-5v and -7v expression did not correlate with survival. One hundred percent of metastatic tumors to LNs were immunoreactive with CD44-3v and only 1/30 normal LN had CD44-3v expression. Eighty percent of metastatic tumors to LNs were immunoreactive for CD44-4v. However, 3 LNs without tumor were also immunoreactive with CD44-4v. CONCLUSION: CD44-4v is a potential molecular marker of disease recurrence in vulvar carcinoma. A larger multiinstitutional study is needed to evaluate the specificity of CD44-3v expression in LN metastasis. If a larger scale study confirms our findings, a CD44-3v antibody could be used for radioimmunoimaging of occult lymph node metastases in patients with vulvar cancer.     

FHIT在宫颈癌及宫颈上皮内瘤变的表达及意义

目的:探讨在宫颈癌和宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)发生中脆性组氨酸三联体(fragile histid ine triad,FHIT)基因表达异常的作用及与HPV感染的关系。方法:用免疫组化法检测67例宫颈癌、42例CINⅢ和35例正常宫颈上皮组织的FHIT的表达。用PCR法检测宫颈癌石蜡组织中的HPV DNA,并用直接测序法或反向核酸杂交法对HPV分型。结果:正常宫颈组织中FHIT基因表达下调率为8.6%,CINⅢ组为28.57%,宫颈癌组为46.27%,差异均有统计学意义(P<0.05)。CINⅢ组FHIT蛋白表达下调率虽比宫颈癌组为低,但组间无统计学差异(P=0.66)。67例宫颈癌病例中,高危型HPV感染阳性者的FHIT表达下降或缺失占55.32%,明显高于无高危型HPV感染者(20%)(P<0.05)。宫颈癌患者的年龄、临床分期、肿瘤组织学分级、肿瘤浸润深度和淋巴结转移与FHIT蛋白表达均无明显相关(P>0.05)。FHIT表达下调或缺失31例宫颈癌患者的5年生存率为77.1%,FHIT正常表达36例的5年生存率为79.3%(P>0.05)。结论:FHIT在宫颈癌及CINⅢ中的表达明显下调,可能与HPV感染协同在宫颈癌的发生中起了重要作用。而FHIT在宫颈癌发展中的作用及与预后的关系,有待大样本的进一步研究。     

p14ARF和p16在宫颈癌及宫颈上皮内瘤变中的表达及意义

目的:探讨抑癌基因p14ARF与p16在宫颈癌及宫颈上皮内瘤变(cervical intraepithelial neoplasia,CIN)组织中的表达及意义。方法:应用S-P免疫组化方法检测p14ARF、p16基因在8例正常宫颈组织、18例CIN1、35例CIN2/3和46例宫颈鳞状细胞癌(squamous cell carcinoma,SCC)中的表达。结果:正常上皮组织,p14ARF和p16无表达;46例SCC、35例CIN2/3中p14ARF和p16蛋白共表达阳性,且二者在SCC中表达显著高于CIN2/3(P<0.05);CIN1中p14ARF、p16表达阴性,仅1例CIN1中p14ARF在近基底细胞中呈弱阳性表达。在CIN2/3中,p14ARF表达局限于近基底膜处,p16则主要表达于上皮细胞的中、上层。p14ARF在低分化癌中和淋巴结转移癌中表达较高,而p16则在Ⅰ期SCC中表达较高。结论:p14ARF可能成为继p16之后更好的宫颈肿瘤标志物。     

宫颈癌组织中DNA修复基因06-甲基鸟嘌呤-DNA甲基转移酶启动子区过甲基化研究

目的:研究宫颈癌中06-甲基鸟嘌呤-DNA甲基转移酶(06-Methylguanine-DNAMethyltransferase,MGMT)基因甲基化状态及其mRNA的表达,探讨MGMT基因甲基化与其基因表达缺陷的关系。方法:用甲基化特异性PCR(MSP)、半定量逆转录聚合酶链反应(RT-PCR)法检测4株宫颈癌细胞、15例正常宫颈组织、20例宫颈上皮内瘤变及38例宫颈浸润癌组织中MGMT基因启动子区过甲基化状态及其mRNA的表达,同时分析MGMT基因甲基化与宫颈癌病理分级、临床分期及淋巴转移之间的关系。结果:4株宫颈癌细胞、正常宫颈组织及CINⅠ组织中无MGMT基因甲基化,MGMT甲基化在CINⅡ~CINⅢ组织中占27%,浸润性宫颈癌中占31%。MGMT基因甲基化在不同的病理分级(P=0.263)和临床分期(P=0.342)中差异无显著性,在有无盆腔淋巴结转移上,差异有显著性(χ2=7.785,P=0.005)。所有MGMT甲基化的癌组织及CIN组织均无MGMTmRNA表达,而所有非MGMT甲基化癌组织、CIN组织和正常宫颈组织均有MGMTmRNA表达。结论:宫颈癌中MGMT基因启动子区异常甲基化是导致此基因表达缺陷的主要原因。