摘要
背景及目的
宫颈癌是最常见的妇科恶性肿瘤之一,在发展中国家妇女中其发病率居第一位。近年来,年轻妇女的宫颈腺癌发病率呈上升趋势,其比例已占宫颈癌病例总数的19.4%。宫颈腺癌的病因和发病机制不清,其临床及分子生物学特性不同于宫颈鳞癌,患者5年生存率较宫颈鳞癌低,预后差。因此,宫颈腺癌已成为妇科肿瘤领域的研究热点。目前研究证实,癌基因的激活和抑癌基因的失活在肿瘤的发生发展中起到关键作用,CyclinD1是一种和细胞周期调节有关的癌基因,而P27是目前研究较多的一种抑癌基因,在胃癌、肝癌、乳腺癌等多种恶性肿瘤中都发现了CyclinD1及P27的异常表达。近年来国内外在宫颈癌中的癌基因及抑癌基因的研究大多是以宫颈鳞癌为主体进行的,在分子水平上对宫颈腺癌单独进行研究者很少。关于宫颈腺癌及宫颈腺上皮内肿瘤(cervical glandularintraepithelial neoplasia,CGIN)中CyclinD1表达的研究国内外尚未见报道,P27在宫颈腺癌及CGIN中的表达报道很少。本研究通过对CyclinD1和P27在宫颈腺癌和CGIN中的表达的检测,分析其与宫颈腺癌发生发展的关系,期望CyclinD1和P27联合检测可作为简单有效的、可以预测临床和预后的分子标志物。
材料与方法
收集郑州大学第一、三附属医院和郑州市妇幼保健院病理科因宫颈恶性肿瘤手术切除标本的存档蜡块。全部蜡块经3μm切片和HE染色,由两位病理专家重新阅片确定诊断,挑选出56例宫颈腺癌(高分化腺癌15例、中分化腺癌21例、低分化腺癌20例)和30例CGIN。24例正常宫颈腺上皮组织来源于因子宫肌瘤手术切除的标本。整理宫颈腺癌的临床资料,包括临床分期及淋巴结转移情况。
采用免疫组化(SP)法分别检测56例宫颈腺癌、30例CGIN、24例正常宫颈腺上皮组织中CyclinD1及P27的表达情况,并分析其与宫颈腺癌的分化程度、临床分期及淋巴结转移的关系。
利用SPSS11.5统计分析软件处理数据。两样本率的比较采用四格表资料x~2检验;多样本率的比较采用行列表资料的x~2检验;相关性检验用Spearman相关分析。以α=0.05为检验水准。
结果
1.CyclinD1在宫颈腺癌、CGIN和正常宫颈腺上皮组织中表达的阳性率分别为62.50%、26.67%和0.00%。宫颈腺癌组织中CyclinD1的阳性表达率均明显高于CGIN及正常宫颈腺上皮组织,差异有统计学意义(P＜0.05),CGIN中CyclinD1的阳性表达率明显高于正常宫颈腺上皮组织,差异有统计学意义(P＜0.05)。
2.CyclinD1在高、中和低分化宫颈腺癌中的阳性表达率分别是26.67%、61.90%和90.00%,三者之间比较,差异有统计学意义(P＜0.05)。临床Ⅰ～Ⅱ期和Ⅲ～Ⅳ期宫颈腺癌,CyclinD1的阳性表达率分别是48.00%和74.19%,差异有统计学意义(P＜0.05)。淋巴结转移组和无淋巴结转移组CyclinD1的阳性表达率分别是77.78%和48.28%,差异有统计学意义(P＜0.05)。
3.P27在宫颈腺癌、CGIN和正常宫颈腺上皮组织中表达的阳性率分别为30.36%、53.33%和91.67%。宫颈腺癌组织中P27的阳性表达率均明显低于CGIN及正常宫颈腺上皮组织,差异有统计学意义(P＜0.05)。CGIN中P27的阳性表达率明显低于正常宫颈腺上皮组织,差异有统计学意义(P＜0.05)。
4.P27在高、中和低分化宫颈腺癌中的阳性表达率分别是66.67%、28.57%和5.00%,差异有统计学意义(P＜0.05)。临床Ⅰ～Ⅱ期和Ⅲ～Ⅳ期宫颈腺癌P27的阳性表达率分别是51.72%和19.36%,差异有统计学意义(P＜0.05)。淋巴结转移组和无淋巴结转移组P27的阳性表达率分别是14.81%和44.83%,差异有统计学意义(P＜0.05)。
5.56例宫颈腺癌组织中,CyclinD1与P27表达均阳性者5例,均阴性者9例;CyclinD1阳性、P27阴性者30例;CyclinD1阴性,P27阳性者12例;二者在宫颈腺癌组织中的表达呈负相关关系(r_s=-0.451,P＜0.05)。
结论
1.CyclinD1的高表达和P27的低表达与宫颈腺癌的发生、发展密切相关。
2.CyclinD1与P27的异常表达与宫颈腺癌的分化程度、临床分期和淋巴结转移均有关。二者可望成为宫颈腺癌恶性程度和预后判断的分子指标。
3.CyclinD1与P27在宫颈腺癌中的表达呈负相关关系。二者可能在宫颈腺癌的发生发展过程中起协同作用。
Background and objective
The cervical cancer is one of most common gynecologic malignant tumor,its incidence is the first in the developing nation.In recent years the study report demonstrated that the young woman's incidence of cervical adencarcinoma assumed the trend of increase,its proportion has accounted for the cervical cancer case of illness total 19.4%.Because pathogenesis of the cervical adenocarcinoma is unclear, its clinical and the molecular biology characteristic is different with cervical squamous cell carcinoma.In the cervical adenocarcinoma the patient 5 years survival rate is lower,prognosis is worse,therefore cervical adenocarcinoma is focus in gynecology malignant.Oncogenes activation and anti-oncogene inactivation is important in development of tumor.CyclinD1 is a oncogenes to adjust cell cycle.P27 is a important anti-oncogene.At present,several studies had discovered CyclinD1 and P27 abnormal expression in the many kinds of malignant tumor,as gastric cancer, liver cancer,and breast cancer so on.The two kind of protein expression are correlated to the malignant tumor.CyclinD1 and P27 have become a focus.In recent years the research to oncogenes and anti-oncogene concentrates to cervical squamous cell carcinoma.There are very few studies of the molecular level to the cervical adenocarcinoma.It has been not yet seen that the CyclinD1 expression research report in domesticthe and foreign about cervical adenocarcinoma and cervical glandular intraepithelial neoplasia,P27 expression report is very few in the cervical adenocarcinoma and cervical glandular intraepithelial neoplasia.To study expression of CyclinD1,P27 in cervical adenocarcinoma and cervical glandular intraepithelial neoplasia.To analyze the relationships between CyclinD1,P27 and development, progression of cervical adenocarcinoma.To judge CyclinD1 and P27 may be simple effective molecule marker that has the extremely significance to forecast prognosis through research.
Materials and methods
56 cases of cervical adenocarcinoma,30 cases of cervical glandular intraepithelial neoplasia and 24 cases of normal cervical glandular epithelium tissue from the First affiliated hospital of Zhengzhou University,the third affiliated hospital of Zhengzhou University and the Zhengzhou women and children's hospital.56 cases of cervical adenocarcinoma include 15 cases of well differentiated,21 cases of moderately differentiated and 20 cases of poorly differentiated.24 cases of normal cervical glandular epithelium tissue come from patient of total hysterectomy for hysteromyoma.After slicing 3μm to all cases,the HE stain.All cases were identified by two pathologists.To analysis its clinical material include of the clinical stage, lymphatic metastasis.
The expression of CyclinD1 and P27 protein were detected in 56 cases of cervical adenocarcinoma,30 cases of cervical glandular intraepithelial neoplasia and 24 cases of normal cervical glandular epithelium tissue by immunohistochemistry.To analyze the pathogenesis of cervical adenocarcinoma.To discussion the relationship bewteen the expression of CyclinD1 and P27 and the pathological grade,the clinical stage, lymphatic metastasis of cervical adenocarcinoma.
All the data were analyzed by SPSS11.5 statistical package,the count information calculated the positive rate.The comparision of positive rate uses the Chi-square test,the mean of more than two groups uses R×C Chi-square test,The relation of two variable are analyzed by Spearman's correlation analysis.The level of significant difference wasα=0.05
Results
1.The positive expression rate of CyclinD1 was respectively 62.50%,26.67%,and 0.00%in cervical adenocarcinoma,cervical glandular intraepithelial neoplasia, normal cervical glandular epithelium tissue.The positive rate was significantly higher in cervical adenocarcinoma and cervical glandular intraepithelial neoplasia than that in normal cervical glandular epithelium tissue(P＜0.05),The positive rate was significantly higher in cervical adenocarcinoma than that in cervical glandular intraepithelial neoplasia,a significant difference between them(P＜0.05).
2.The positive expression rate of CyclinD1 was respectively 26.67%,61.91%and 90.00%in cervical adenocarcinoma that well differentiated,moderately differentiated and poorly differentiated,a significant difference between them(P＜0.05)。The positive expression rate of CyclinD1 was respectively 48.00%,74.19%in cervical adenocarcinoma in clinicalⅠ～Ⅱissue andⅢ～Ⅳissue,the difference has the remarkable statistics significance(P＜0.05).The positive rate of the expression of CyclinD1 in the group with lymph node metastasis and in the group without lymph node metastasis was 77.78%,48.28%,a significant difference between them(P＜0.05).
3.The positive expression rate of P27 was respectively 30.36%,53.33%and 91.67%in cervical adenocarcinoma,cervical glandular intraepithelial neoplasia, normal cervical glandular epithelium tissue.The positive rate was significantly lower in cervical adenocarcinoma and cervical glandular intraepithelial neoplasia than that in normal cervical glandular epithelium tissue,a significant difference between them (P＜0.05).
4.The positive expression rate of P27 was respectively 66.67%,28.57%and 5.00%in cervical adenocarcinoma that well differentiated,moderately differentiated and poorly differentiated,a significant difference between them(P＜0.05).The positive expression rate of P27 was respectively 51.72%,19.36%in cervical adenocarcinoma in clinicalⅠ～Ⅱissue andⅢ～Ⅳissue,the difference has the remarkable statistics a significance(P＜0.05) The positive rate of the expression of P27 in the group with lymph node metastasis and in the group without lymph node metastasis was14.81%,44.83%,a significant difference between them(P＜0.05)
5.56 cases of cervical adenocarcinoma,5 cases are positive of CyclinD1 and P27,9 cases are negative,30 cases of CyclinD1 are positive and P27 are negative,12 cases of CyclinD1 are negative and P27 are positive.Cervical adenocarcinoma correlative analysis showed the expression of CyclinD1 has a negative relationship with the expression of P27(r_s=-0.451,P＜0.05).
Conclusions
1.Generation and development of cervical adenocarcinoma is closely correlated to positive expression of CyclinD1 and negative expression of P27.
2.Abnormal expression of CyclinD1 and P27 is correlated to the histological grade,clinical stage and lymph node metastasis in cervical adenocarcinoma. Expression of CyclinD1 and P27 may be help judgement prognosis of cervical adenocarcinoma.
3.The expression of CyclinD1 and P27 was reverse correlated.CyclinD1 and P27 may be have synergistic in development and progression of cervical adenocarcinoma.
引文
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