【作者】 杨建柱；

【导师】 张祥宏； 王凤荣；

【作者基本信息】 河北医科大学 ， 病理学与病理生理学， 2002， 硕士

【摘要】 目的：子宫颈癌(cervical carcinoma)是常见的妇科恶性肿瘤之一，其发病率在发展中国家仍居首位，而且近年来其发病有年轻化趋势。在过去的几十年里，人们在宫颈癌的不同方面进行了许多研究，但迄今为止，关于宫颈癌的发病机制仍不十分清楚。 EP-CAM(epithelial cell adhesion molecule)，也称为17-A，ESA，EGP40，是一种由GA-733-2基因编码的分子量为40KDa的跨膜糖蛋白，作为嗜同种的钙非依赖性的上皮细胞间粘附分子在上皮癌变过程中发挥着作用。β-连接蛋白(β-catenin)是一类细胞骨架蛋白，它既能与E-钙粘蛋白(E-cadherin)结合介导同型细胞间的粘附，与肿瘤的侵袭转移密切相关；也参与APC／β-catenin／Tcf／Lef-1构成的Wg／Wnt信号转导通路，与胚胎发育及肿瘤的发生有关。 研究发现宫颈癌发病与人类乳头瘤病毒(humanpapillomavirus，HPV)感染有关。到目前为止，已发现大约100种不同类型的HPV，其中13种与宫颈癌有关。根据HPV亚型与女性生殖道恶性肿瘤的关系，将HPV分为低危型和高危型，其中高危型HPV-16型与子宫颈鳞状细胞癌的关系最为密切。尽管HPVs在宫颈 中文摘要癌的发生中发挥了重要作用，但是只有一小部分感染了高危型HPVS的宫颈上皮将发展成浸润癌，说明还有其他因素的参与。 EP－CAM禾p－catenin在乳腺癌、喉癌等肿瘤中的表达及临床意义已见报道，但其在宫颈癌发生发展中的作用以及与HP V 16感染之问的关系尚不清楚。 本研究试图通过检测正常宫颈鳞状卜皮、宫颈上皮内瘤变（CeWical intraeplthellal neoplasm，CIN）、宫颈浸润性鳞状细胞癌中 EPCAM、日七atenin的表达及HPV的感染情况，来探讨 EPCAM、p《atenin在宫颈癌变过程中的意义及其与临床病理特征、HPV感染的关系，从而进一步阐明宫颈癌的发病机理，为宫颈癌的诊断、治疗提供理论依据c 方法：本研究采用免疫组织化学的人法，检测了N例l卜常宫颈鳞状卜皮、3n 宫颈卜皮内瘤变（包括CINI 14例，CINZ 10例，CIN3 8例）和 38例宫须浸润性鳞状 细胞癌 中 EPCAM、p－catenin的表达情况，问时利川聚合酶链反应oCR）技术对卜述病例进行＊＊V 16型感染的检测，并分析了这两种检测指标之间及其与各种临床南理囚素、＊＊V16感染之问的相关性。 结果：1．＊卜＊＊M的表达。睛况：14例上常宫颈卜皮基底层细胞 EP（AM缺乏表达或者弱表达c从 CIN到宫颈癌，EP（AM 在细胞膜的过表达率分别为7．14％、20＊0％、62．50％、55＊6％，其中 CIN3组或宫颈鳞状细胞癌组EPCAM的过表达率明显高于正常组 中文摘要 和 CINI组o．001卜但 EPCAM的过表达率在 CIN3 和宫颈鳞癌组之问无显著性差异（PDeo刀5人2．p ＜atenin的表达情况：14例正常宫颈鳞状上皮基底层细 胞膜呈棕黄色染色，但胞浆和胞核未见着色。在CIN 及其鳞癌组部分病例中可见p七atenin的异常表达（包 括p七atenin 的表达消失或在胞浆和／或胞核中出现异 常积聚入从正常宫颈上皮、CIN到宫颈鳞癌，8六atenin 臼异常表达率逐渐递增（0，28．57o，40．00o，62．50O， 84＊ 1％ ），其中，CINZ、CIN3、宫颈鳞屈组 p－catenin 的异常表达率均高于正常宫颈上皮组和 CINI组Twt 0刀5）；宫颈鳞癌组 p《atenin的异常表达率分别高于 CINI、CINZ组（Pwto．001X 但宫颈鳞癌组与CIN3组 之间 p｛atenin的异常表达率无显著性差异（P＞0刀5人 3．HPV型 DNA检测情况：正常宫颈鳞状上皮。 CINI。CINZ、CIN3 及宫颈浸润性鳞状细胞癌组织 HPV16型 DNA检出率分别为 0、0、30o、75o、50o。 CINZ、CIN3和宫颈鳞癌组 HPV 型 DNA检出率均 高于正常宫颈鳞状上皮和 CINI组（Prto．05），而CIN3 组p V 16型＊＊A检出率与宫颈鳞癌组相比二者之间 无显著性差异（P＞0刀5 ）o 4．宫颈鳞癌中 EP（AM的 过表达、卜比代山n的异常表达、HP V16感染三者之间 的关系：HPV感染与 EP（AM过表达、e｛atenln 的异常表达均无关，而EPCAM的过表达与卜catenin 的异常表达之间存在相关性0—0刀7人 5．宫颈鳞癌 中 EPCAM、日．catenin、HPV型 DNA的表达与年 3 中文摘要龄、肿瘤大小、分化程度、临床分期、淋巴结转移情况之间的关系：除E卜C＊M在低分化鳞癌中的过表达率明显高于中、高分化癌外（P t 0刀of人 三者的表达与临床病理因素之间未发现有相关关系。 结论：本研究结果表明：1．EP（AM的过表达率。p《atenin的异常表达率从正常宫颈鳞状卜皮、CIN至宫颈鳞状细胞癌逐渐增高。2．HPV 6DNA在正常宫颈组织中未见阳性，但随 C IN到宫颈鳞癌，其检更多还原

【Abstract】 Objective: Cervical carcinoma is one of the most frequently seen malignancies in female with high incidence in the developing countries. Recently, there is an increasing tendency in the incidence among younger women. In the past decades, many studies on different aspects have been carried out on cervical carcinoma, but up to now, the carcinogenesis of cervical carcinoma is still not clear enough.Epithelial cell adhesion molecule (EP-CAM), also called 17-1 A, ESA, EGP40, is a 40KDa epithelial transmembrane glycoprotein, encoded by the GA733-2 gene, to function as a homophilic cell adhesion molecule, in a Ca2+ - independent manner in benign and malignant epithelial cells. Beta - catenin is a kind of cell bone protein. It binds to E-cadherin and mediates the adhesion among the same kinds of cells, highly associated with tumor’s invasion and metastasis. On the other hand, Beta-catenin is involved in the Wg/Wnt signaltransductionpathway, composed by APC/ -catenin/Tcf/Lef-1, associated with embryo growth and carcinogenesis of carcinoma.Human papillomaviruses (HPVs) were found to be associated with the incidence of cervical carcinoma. Of the about 100 different types of HPV that have been categorized to date, approximately thirteen were associated with cervical carcinoma. Based on the relationship between subsets of HPVs and female genital cancers, HPVs were categorized into "high - risk’ HPVs and ’low - risk’ HPVs. Of the ’high - risk’ HPVs, HPV-16 is highly associated with cervical squamous cell carcinoma. It has been generally accepted that HPVs play an important role in the carcinogenesis of cervical carcinoma. However only a small proportion of cervical intraepithelial lesions infected with ’high - risk" HPVs will progress to invasive cervical carcinoma, which indicates the involvement of additional factors.The clinical significance of the expression of EP-CAM and beta-catenin in breast cancer and laryngeal cancer has been reported. The putative contribution of them in the carcinogenesis of cervical carcinoma and their relationship with HPV-16 infection was still unclear.To explore the possible roles of EP-CAM and beta-catenin expression in the carcinogenesis of cervicalcarcinoma and elucidate the relationship between their expression and HPV-16 infection, the expressions of EP-CAM and beta-catenin as well as existence of HPV-16 DNA in normal cervical epithelium, CIN and cervical invasive carcinoma were investigated in this study.Methods: EP-CAM, beta-catenin expressions were studied with immunohistochemical stainning in 14 cases of normal cervical epithelium, 32 cases of CIN and 38 cases of cervical invasive squamous cell carcinoma. At the same time, HPV-16 DNA was detected using polymerase chain reaction (PCR) in these cases. The relationship between the expression of EP-CAM and beta-catenin and clinical pathological features as well as HPV-16 infections was also studied.Results: 1. EP-CAM expression: No or very weak expression of EP-CAM was found in 14 cases of normal cervical epithelium, while over-expressions could be found in some CIN and carcinoma cases. The over-expression rates of EP-CAM was 7.14%, 20.00%, 62.50%, 55.26% for CIN1, CIN2,CIN3 and carcinoma groups respectively. The rates of over-expression of EP-CAM in CIN3 and cervical carcinoma groups were all significantly higher than these in normal epithelium and CIN1 groups (P < 0.001). There is no significant difference between CIN3 group and cervical squamouscell carcinoma group in the over-expression rates(P> 0.05). 2. Beta-catenin expression: beta-catenin was localized only on the plasma membrane of the basal and parabasal layer cells in normal cervical squamous epithelium. In some cases of CIN and squamous cell carcinoma cases, aberrant expression (no expression, cytoplasmic or/and nuclear expressions) of beta-catenin was observed. Aberrant expression rates of beta-catenin increased from normal epithelium, CIN to cervical carcinoma. The aberrant expression rate for CIN1, CIN2, CIN3 and carcinoma gr更多还原