论文标题:宫颈上皮内瘤样病变及宫颈癌中p16蛋白、细胞周期素D_1的表达及相关性
Expression of p16 and CyclinD1 in Cervical Intraepithelial Neoplasia and Cervical Cancer and Their Correlation
论文作者 万俊
论文导师 崔满华,论文学位 硕士,论文专业 妇产科学
论文单位 吉林大学,点击次数 146,论文页数 48页File Size422k
2004-04-01论文网 http://www.lw23.com/lunwen_62569177/ 2型糖尿病;变异;胰岛素抵抗; β细胞; 线粒体基因;单核苷酸多态性
Type 2 diabetes; variation insulin resistance; β-cell; SNP; mtDNA genes
宫颈癌是全球妇女恶性肿瘤中仅次于乳腺癌的第二个最常见的恶性肿瘤,宫颈上皮内瘤样病变(CIN)是与宫颈癌相关的一组癌前病变,其反映宫颈癌发生发展中的连续过程。近年来的研究认为,肿瘤是一类细胞周期性疾病。在细胞增殖周期中,最主要的调控点是G1期与S期之间的调控点。因而,一旦通过这个点,细胞周期进程就变的不可逆。此调控点受控于细胞周期蛋白 (cyclins)和细胞周期蛋白依赖性激酶抑制因子 (cdkIs)对细胞周期蛋白依赖性激酶 (cdks)的正负调节作用,即正常细胞对G1 →S的调控同时需要cyclinD1 的正调控和p16的负调控。p16的失活和/或cyclinD1 的过表达 ,可能引起细胞异常增殖和分化失控,最终导致肿瘤的发生。本研究采用免疫组化测定宫颈癌及宫颈上皮内瘤变组织中p16蛋白。cyclinD1蛋白,旨在探讨宫颈癌变过程中p16和cyclinD1 的变化及其相互关系,为临床早期评估宫颈上皮内瘤变的恶变倾向,监测病情,判断预后提供可靠的依据。方法:收集宫颈癌41例, CINⅠ11例,CINⅡ11例,CINⅢ24例。全部病例手术前均未做放疗。化疗。本资料41例宫颈癌的临床分期为Ⅰ-Ⅲ期,其中有25例病理检查证实有不同程度的盆腔淋巴结转移。此外,选择正常宫颈组织12例作对照。结果判定:p16蛋白的阳性表达为细胞核,cyclinD1蛋白阳性表达为细胞核;参照Shimizu等的判断标准。统计学处理 :采用 χ2 检验 ,四格表确切概率法及相关性分析。结果及讨论： 1. p16蛋白在宫颈上皮内瘤变及宫颈癌中的表达及意义p16是一种新型抑癌基因,在细胞周期中p16暨是固有的调节者 ,又是抑制肿瘤生长的关键成分 。本研究中正常宫颈组织中p16表达最强,随着正常宫颈组织→宫颈上皮内瘤样病变→宫颈癌的演进 ,其阳性表达率逐渐降低，差异有显著性，表明宫颈癌中可能存在p16基因的缺失和突变 ,且在不同分化程度的肿瘤组织中存在明显不同，p16表达强度的变化在一定程度上与细胞的恶性倾向有关 ,可以推测p16基因在宫颈癌组织中表现为失活 ,是宫颈癌发生发展过程中较晚的分子事件。因此 ,p16失活和突变,可能引起细胞异常增殖和分化失控 ,最终与其它致癌因素一起导致宫颈癌的发生。宫颈上皮内瘤变组内，p16蛋白的表达也随着CINⅠ→CINⅡ→CINⅢ的演进，阳性率逐渐降低， CINⅠ组阳性率明显高于CINⅢ组及原位癌组，无统计学意义，可能与例数过少有关，也可能与实验中出现的假阳性有关。宫颈上皮内瘤样病变的转归问题一直是多年来临床十分关注的问题，通常CINⅠ时，可出现好转和恢复，随着不典型程度的加重，则回复正常和不变者区分率降低，而发展为原位癌者则升高。本组数据也可以证明这点，CINⅠ阳性率最高, 而CINⅡ及CINⅢ相差不多且越接近宫颈癌,说明在中、重度宫颈不典型增生组织中，p16蛋白可能已经发生了一定数量上的失活或突变，但还没达到质变的程度。 本研究显示，p16蛋白的阳性表达率随宫颈癌组织学分化程度升高而呈下降趋势，且差异有显著性，可以看出p16蛋白的表达与宫颈癌的细胞分化程度有关，说明p16蛋白的表达可作为判断肿瘤细胞恶性程度的标志。p16蛋白的表达与宫颈癌淋巴结转移有关，有淋巴结转移的p16蛋白的阳性表达率明显低于无转移的，差异有显著性，这提示p16蛋白可以作为判断宫颈癌预后的一个新指标。另外，本资料中p16蛋白的阳性表达率与宫颈癌的临床分期无关，统计学上无意义，但仍存在着随临床期别的增高阳性表达率下降这一趋势.2.Cyclin D1蛋白在宫颈上皮内瘤变及宫颈癌中的表达及意义本研究结果显示, cyclinD1蛋白随着正常宫颈→宫颈上皮内瘤变→宫颈癌的演进,其阳性表达率逐渐升高,即宫颈癌组最高 (70.7 % ) ,宫颈上皮内瘤样病变组 (48.6%) ,正常宫颈组织 (16.7 %)依次减低,差异有显著性,且两两比较亦均有显著性差异,证明 Cyclin D1 的表达水平与肿瘤的恶性程度相关 ,支持 Cyclin D1作为原癌基因参与细胞周期代谢及调控的理论 。从本研究中还可看出，cyclinD1蛋白在宫颈上皮内瘤变组织中的阳性表达率也随着病变的进展而升高,宫颈原位癌为66.7%。从这一数据可以看出CINⅡ和CINⅢ已有cyclinD1 明显表达阳性,说明cyclinD1可能与宫颈癌的发生有关 ,且可能是宫颈癌发生过程中的早期分子事件[15]，这意味着cyclinD1 基因蛋白有可能作为临床早期发现宫颈癌的免疫学指标。本研究中cyclinD1蛋白的表达随着宫颈癌的临床分期的升高，阳性率升高，临床Ⅲ期的明显高于前两期，且两两之间比较差异有显著性，另外在有淋巴结转移的宫颈癌组，cyclinD1蛋白的阳性表达率也高于无淋巴结转移的，差异有显著性，这为我们判断预后提供了很好的辅助依据，临床期别高的，有淋巴结转移的，cyclinD1蛋白表达率高，预后差。cyclinD1蛋白的表达与宫颈癌的细胞分化程度有关，在高分化、中分化及低分化组的阳性表达率分别为(33.3﹪,76.5﹪,86.7﹪),差异有显著性。分别两两比较，高分化组与低分化组之间，高分化组与中分化组之间差异均有显著性，中分化与低分化之间差异无显著性，这可能是样本量的问题造成的，有待继续探讨。3. p16蛋白异常与cyclinD1蛋白异常在宫颈癌发生发展中的相互关系cyclinD1单独作用
In the world ,cervical cancer is the most common cancer in women’s cancer ,second to breast cancer.Cervical intraepithclial neoplasia(CIN) is a group of precancerous lesion correlated with invasive carcinoma of cervix.It reacts the successive process of cervical cancer.In recent years,most studies show that neoplasia is a category of diseases about cell cycle.In the cellproliferation cycle,The check point between G1 phase and S phase is the most important one.Therfore,once passes through the check point ,the process of cell cycle turns inconvertible.The check point is controlled by cyclins and cdkIs .cyclinD1’s positive control and p16’s negative control are the necessity of normal cell to the G1-S. The inactivation of p16 and (or) the overexpression of cyclinD1 can cause cells to proliferate abnormally and differentiate uncontrolled,then cause neoplasia.In this study ,cyclinD1and p16 were examined in different cervical cancer and precancerous lesions to investigate the expression of cyclinD1and p16 in the carcinogenesis of cervical cancer and to study the correlation of cell-cycle regulators between cyclinD1 and p16.It will offer reliable basis for evaluating tendency of canceration in clinical earlier period,monitoring patient’s conditon and judging prognosis.Method:collect 41 cases of invasive carcinoma of cervix(ICC), 11 cases of CINⅠ,15 cases of CIN Ⅱ,24 cases of CINⅢ.All the cases were cofirmed by pathology and weren’t treated by radiotherapy or chemotherapy before surgery.The clinical stages of 41 cases of ICC were divided intoⅠ,Ⅱ,Ⅲ,there are 25 cases of which confirmed by pathology had lymphocyte metastates in different degrees.And collect 12 cases of normal cervicixs as contrast group.Result’s standard: statistics management:use chi-square test,exact probabilities in 2×2 table and correlation analysis.Results and discussion:the expression of p16 in CIN and cervical cancer p16 is a new type of anti-oncogene,in the cell-cycle ,it is not only an intrinsical regulator but also a key component to restrain growth of tumour.In this study ,p16 has the highest expression in normal cervix.Among the groups of the normal cervix and CIN and cervical cancer, the positive immunostaining rate for p16 showed a descending tendency ,the difference is remarkable.It showed us that the deletion and mutation of p16 gene may exist in cervical cancer.And it has distinctive difference in tumours of different differentiation.So the expression intensity of p16 is correlated with the malignant tendency of cell.We may suspect the inactivation of p16 is a late molecule affair in the carcinogenesis of cervical cancer.So the inactivation and mutation of p16 can cause cells to proliferate abnormally and differentiate uncontrolled,then cause cervical cancer with other carcinogenic factors ultimately.Among the groups of CIN, the positive immunostaining rate for p16 showed a descending tendency ,the difference is remarkable. The positive immunostaining rate in group of CINⅠis obviously higher than the one in group of carcinoma in situ of cervix,the difference is not remarkable,it may be owing to the sample size ,also owing to the flase positive in the trial.The conversion of CIN has been paid close attention to in the clinical work..Usually , CINⅠ can take a turn for the better and recover.With the severity of atypical hyperplasia, turning to cervical carcinoma has the higher possibility.This data can also prove it.In the issues of CINⅡand CINⅢ,it is possible that p16 has occur to inactivation and mutation,but still doesn’t achieve the the degree of nature change.The study show:the positive immunostaining rate for p16 showed a descending tendency with the advance of histological differention,the difference is remarkable.So the expression of p16 may be related with the histodifferentiation in cervical cancer,then it can take as a marker to judge the malignant degree of tumor cells.The expression of p16 is correlated with lymphatic metastasis of cervical cancer.The expression of p16 in group with lymp
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