【作者】 侯瑞杰；

【导师】 卢爱妮；

【作者基本信息】 郑州大学 ， 妇产科学， 2012， 硕士

【摘要】 背景与目的在世界范围内,宫颈癌是妇女癌症中仅次于乳腺癌而位居第二的恶性肿瘤。在我国宫颈癌是最常见的妇科恶性肿瘤,且发生率有继续增加和年轻化趋势。目前,其发病机制尚不完全清楚。癌基因的激活、抑癌基因的失活是肿瘤发生的重要机制之一。脆性组氨酸三联体(fragile histidine triad, FHIT)是一种候选抑癌基因。FHIT蛋白通过诱导细胞调亡、调控细胞周期,参与微管形成等发挥抑癌作用。它的表达对肿瘤的发生、发展、肿瘤分化、侵袭性和转移有着重要影响。鼠双微体2(murine double minute2, MDM2)为癌基因,编码泛素-蛋白连接酶,MDM2基因扩增或MDM2蛋白过度表达可以负性调节p53蛋白的稳定性和转录活性,限制其肿瘤抑制功能的发挥,使细胞获得更强的促进细胞转化和恶变的能力。本文旨在研究FHIT和MDM2在慢性宫颈炎宫颈组织、宫颈上皮内瘤变(CIN)、宫颈鳞癌组织中的表达,及其与宫颈鳞癌临床病理特点的关系,并探讨FHIT和MDM2在宫颈鳞癌发生发展中的作用。材料与方法1、实验分组组织标本均来源于郑州大学第二附属医院病理科,选取2009年9月至2011年7月库存标本,均经过石蜡包埋法处理,其中宫颈鳞状细胞癌的组织标本50例,宫颈上皮内瘤变组织标本40例(CIN1为20例,CIN2-3为20例),并取同期住院的(因子宫良性病变行子宫全切术)慢性宫颈炎宫颈组织20例作为对照。所有的宫颈病变患者术前均未接受放疗或／和化疗。2、实验方法应用免疫组织化学即S-P法检测FHIT和MDM2蛋白在慢性宫颈炎、CIN、宫颈鳞癌组织中的表达情况。3、统计方法运用SPSS17.0软件包进行数据的统计学相关的分析,采用x2检验的方法,比较组间的差异,两因子的相关性采用2×2配对资料的关联性分析法进行统计分析,以a=0.05为检验水准,若P<0.05即认为差异有统计学意义。结果1.FHIT蛋白在不同宫颈组织中的表达FHIT蛋白在对照组、CIN组、宫颈鳞癌组组织中的阳性表达水平呈下降趋势,在对照组中的表达明显高于CIN组(χ2=4.335,P<0.05)和宫颈鳞癌组(χ2=22.256,P<0.05),CIN Ⅰ组与CIN Ⅱ-Ⅲ组该蛋白差异表达无统计意义(P>0.05)；CIN组与宫颈鳞癌组组织中FHIT蛋白的差异表达有统计学意义(χ2=12.266,P<0.05)。FHIT蛋白的表达与宫颈鳞癌患者的年龄、临床分期无明显相关性(P>0.05),与组织分化、淋巴转移情况相关(P<0.05)。2.MDM2蛋白在不同宫颈组织中的表达MDM2蛋白在对照组、CIN组、宫颈鳞癌组组织中的阳性表达水平呈上升趋势,在对照组中的表达明显低于CIN组(χ2=5.294,P<0.05)和宫颈鳞癌组(χ2=22.256,P<0.05),CIN Ⅰ组与CIN Ⅱ-Ⅲ组该蛋白无明显差异表达(P>0.05)；CIN组与宫颈鳞癌组组织中MDM2蛋白的差异表达有统计学意义(χ2=14.042,P<0.05)。MDM2蛋白的表达与宫颈鳞癌患者的年龄无明显相关(P>0.05),与临床分期、组织分化、淋巴转移情况相关(P<0.05)。3. FHIT和MDM2在宫颈鳞癌中表达情况的相关性分析得出FHIT和MDM2在宫颈鳞癌组织中表达呈负相关(χ2=16.563,r=-0.576,P<0.01)。结论1. FHIT蛋白可能参与宫颈鳞癌的发生。2.MDM2蛋白可能参与宫颈鳞癌的发生和进展过程。3. FHIT、MDM2蛋白可能与宫颈鳞癌的转移相关。4. FHIT、MDM2蛋白的表达在宫颈鳞癌组呈负相关,提示FHIT蛋白表达降低和MDM2蛋白表达升高可能促进了肿瘤的恶性增殖及转移。更多还原

【Abstract】 Background and PurposeCarcinoma of the cervix is the second most common gynecological malignancy among women worldwide, whose incidence rate is merely lower than breast cancer. In our country there is a rising trend in incident rate and incidence of young patient with cervical cancer. So far the exact etiology and pathogenesis of cervical cancer remains unknown. The activation of oncogene and inactivation of anti-oncogene is one of mechanisms of tumorigenesis.Fragile histidine triad (FHIT) is one of candidate anti-oncogenes. FHIT plays a role by inducing cell apoptosis and regulating cell cycle and participating in formation of microtubules. The expression of FHIT can affect tumor occurrence and development,also differentiation,invasion and metastasis notablely. Murine double minute2(MDM2) is one of oncogenes. The amplification of mdm2gene and over expression of mdm2protein can regulate P53gene negatively and limit its role as a tumor suppressor, acquired ability of facilitating cell transformation and canceration.This article aims to study the expression of FHIT and MDM2in chronic cervicitis, cervical intraepithelial neoplasia (CIN), cervical squamons cell carcinoma,and their clinicopathologic relationships with cervical squamons cell carcinoma, investigating the role of FHIT and MDM2in occurrence and development of cervical cancer.Materal and Methods1. GroupingAll tissue samples were collected from the department of pathology of the Second Affiliated Hospital of Zhengzhou University from September2009to July2011. They were all embeded in paraffin.50cases of cervical squamous cell cancer and40cases of CIN (including20cases of CIN I and20cases of CINⅡ-Ⅲ) were treated as the experimental groups.20cases of chronic cervicitis tissue which were gained by total hysterectomy because of benign uterine diseases were treated as the control group. None of these patients received treatments with rideotherapy and/or chemotherapy before surgery.2. MethodStreptavidin-peroxidase immunostaining (SP) method was used to detect the expression of FHIT and MDM2in the tissues of chronic cervicitis, CIN and cervical squamons cell carcinoma.3. Statistical analysisAll of the data analysis was performed with statisticial software package SPSS17.0version. Chi-square test was applied in comparing differences between experimental group and control group. Correlation between FHIT and MDM2was analysied by using2x2Contingency Table. The standard statistically significance level was alpha=0.05.Results1. The expression of FHITThe positive expression rates of FHIT displayed a decreasing level from chronic cervicitis group,different CIN groups to cervical cancer group.The positive expression of FHIT in chronic cervicitis tissus was significantly higher than in CIN tissues (χ2=4.335, P<0.05) and cervical squamous cell cancer tissus (χ2=22.256, P<0.05).There was no statistically difference between CIN I and CIN II-III(P>0.05).There was statistically differrence between CIN group and squamous cell cancer group (χ2=12.266, P<0.05). The positive expression of FHIT in cervical squamons cell cancer groups was related to histological grading and lymph node metastasis,(P<0.05), which had nothing to do with the pathological type and age (P>0.05).2. The expression of MDM2The positive expression rates of MDM2displayed a increasing level from chronic cervicitis group,different CIN groups to cervical cancer group. The positive expression of MDM2in chronic cervicitis tissues was significantly lower than in CIN tissues (χ2=5.294, P<0.05)and cervical squannous cellcancer tissus (χ2=22.256, P<0.05). There was no statistically difference between CIN I and CIN Ⅱ-Ⅲ (P>0.05).There was statistically differrence between CIN group and squamous cancer group (χ2=14.042, P<0.05). The expression of MDM2in different cervical squamons cancer groups was not corelated with different ages (P>0.05),but significantly related with clinical stage, histological grade and lymph node mestastasis (P<0.05). The positive expression of MDM2in cervical squamons cell cancer groups was related to pathological type,histological grading and lymph node metastasis,(P<0.05), which had nothing to do with age (P>0.05).3. The correlation between FHIT and MDM2in different cervical squa-mous cell cancer tissuesThe expression of FHIT and MDM2were obviously inverse correlation (χ2=16.563,r=-0.576,P<0.01)Conclusions1. FHIT might play an important role in the occurence of cervical squamous cell carcinoma.2. MDM2might participate in the occurence and development of cervical squamous cell carcinoma.3. Both FHIT and MDM2might participate in the metasitasis of cervical squamous cell carcinoma.4. The FHIT expression was negatively correlated to MDM2expression, indicating that loss expression of FHIT and overexpression of MDM2might promote proliferation and metastasis of malignant tumor.更多还原