【作者】 刘露；

【导师】 童英；

【作者基本信息】 中国人民解放军军医进修学院 ， 妇产科学， 2010， 硕士

【摘要】 目的：探讨整合素连接激酶(ILK)、缺氧诱导因子-1α(HIF-1α)、上皮型钙粘蛋白(E-cadherin)及p16在正常宫颈黏膜上皮、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：采用免疫组化技术(SP法)对空军总医院病理科2005年1月～2009年8月宫颈活检及手术切除的病理标本112例,其中CINⅠ级16例,CINⅡ～Ⅲ级38例,浸润癌38例,行ILK、HIF、1α、E-钙粘蛋白和p16蛋白的检测。结果：①从正常宫颈黏膜上皮到CIN再到浸润癌,ILK阳性表达率呈渐进性增高。宫颈癌组织中ILK阳性率明显高于CINⅡ～Ⅲ级,CINⅠ级阳性率明显高于正常宫颈黏膜上皮(P<0.05)。ILK在宫颈癌组织中的表达与患者年龄、FIGO分期、分化程度及有无淋巴结转移无相关性(P>0.05),可能与病例数量偏少及实验假阳性有关。②从正常宫颈黏膜上皮到CIN再到浸润癌,HIF-1α阳性表达率呈渐进性增高,在正常宫颈组织中基本无表达,CINⅠ中显著低于CINⅡ～Ⅲ(P＜0.05),而CINⅡ～Ⅲ又显著低于浸润癌(P<0.01)。HIF-1α的表达与年龄无关,与FIGO分期、分化程度及有无淋巴结转移相关。Ⅲ、Ⅳ期、中低分化及有淋巴结转移的宫颈癌组织中HIF-1α的表达水平均明显高于Ⅰ、Ⅱ期、高分化和的无淋巴结转移的组织(P<0.01)。③E-钙粘蛋白在正常宫颈组织、CINⅠ、CINⅡ-Ⅲ、浸润癌中的阳性表达率呈递减趋势,在正常宫颈组织表达显著高于CINⅠ(P＜0.05),CINⅠ显著高于浸润癌(P<0.05)。随着临床期别的增加,E-钙粘蛋白的阳性表达率呈下降趋势,按不同分化程度比较,癌细胞分化越差,E-钙粘蛋白的阳性率越低。此外,无淋巴结转移宫颈癌中的阳性表达率也显著高于有淋巴结转移(P<0.01)。对于年龄因素,E-钙粘蛋白在宫颈癌中的表达与其无关(P>0.05)。④p16在正常宫颈、CINⅠ、CINⅡ-Ⅲ及宫颈癌组织中表达呈递增趋势,且正常宫颈组织p16蛋白阳性表达率显著低于CINⅠ(P＜0.05), CINⅠ显著低于浸润癌(P<0.05)。p16蛋白在宫颈癌患者年龄组、FIGO分期组和有无淋巴结转移组各组内的阳性表达率均无显著性差异(P>0.05)。在不同分化程度宫颈癌组织中,宫颈癌组织分化程度越低,p16的阳性表达率就越高。⑤ILK、HIF-1α及p16蛋白等信号分子的阳性表达率均与E-钙粘蛋白的阳性表达率呈现负相关。结论：①ILK作为一项较好的细胞增殖标记物,对区分宫颈正常黏膜与各级CIN病变及浸润癌有一定参考价值,但其是否与宫颈癌的生物学行为和恶性程度有关,以及是否有助于临床评估宫颈癌患者的预后,这方面还需要做进一步的研究随访。②对HIF-1α蛋白的检测和研究将有助于宫颈癌的早期诊断及鉴别诊断,并能够预测肿瘤的发展趋势和转移潜能,有望成为一种新的临床诊断指标和肿瘤标记物；宫颈癌中同样存在着HIF-1α/E-钙粘蛋白途径,进一步对HIF-1α/E-钙粘蛋白表达调控机制的研究将为宫颈癌的诊治提供重要线索。③E-钙粘蛋白的异常表达参与了宫颈癌的发生,宫颈癌中E-钙粘蛋白的降表达与ILK、HIF-1α及p16等信号分子过表达均相关,说明多种信号分子和E-钙粘蛋白在宫颈癌变过程中协同发挥细胞恶性转化作用,联合检测多种信号分子及E-钙粘蛋白的表达对了解宫颈癌发生、发展的机制有一定意义。④p16蛋白在宫颈癌的表达明显高于正常宫颈黏膜组织,且在肿瘤早期即发生改变,是一类早期事件。将p16检测作为宫颈癌前病变的辅助筛查,可帮助我们判定宫颈病变是否已经达到CIN,减少宫颈癌的漏诊率,从而进行早期及时的治疗。更多还原

【Abstract】 Objective:To study the expression and clinical significance of ILK, HIF-1α, E-cadherin and p16 in normal cervical epithelium, cervical intraepithelial neoplasia(CIN) and cervical carcinoma.Methods:The expression of ILK, HIF-1α, E-cadherin and p16 in 112 pathological specimens was detected by Immunohistochemistry. The specimens were all obtained by cervical biopsy or excision, including 16 cases of CINⅠ,38 cases of CINⅡ～Ⅲand 38 cases of cervical carcinoma.Results:①From normal cervical epithelium to CIN and then to cervical carcinoma, the positive expression rate of ILK showed gradual increase. The rate in cervical carcinoma was apparently higher than in CINⅡ～Ⅲ, and that in CINⅠwas apparently higher than in normal cervical epithelium(P＜0.05). The expression of ILK did not correlate with the patients’ age, FIGO staging, degree of differentiation and lymph node metastasis(P＞0.05). The reason might be related to the insufficient cases and false-positive results.②From normal cervical epithelium to CIN and then to cervical carcinoma, the positive expression rate of HIF-la increased gradually. There was almost no expression of HIF-1αin normal cervical epithelium. The expression in CINⅠwas apparently lower than in CINⅡ～Ⅲ(P＜0.05), while that in CINⅡ～Ⅲwas apparently lower than in cervical carcinoma(P＜0.01). And the expression of HIF-1αdid not correlate with the patients’ age, but did with FIGO staging, degree of differentiation and lymph node metastasis. The expression in the cervical carcinoma StageⅢandⅣ, moderately or poorly differentiated and with lymph node metastasis was apparently higher than in that StageⅠandⅡ, well differentiated and without lymph node metastasis(P＜0.01). ③The positive expression rate of E-cadherin showed a decreasing trend in turn in normal cervical tissues, CINⅠ, CINⅡ～Ⅲand cervical carcinoma. The rate in normal cervical tissues was apparently higher than in CINⅠ(P＜0.05), and in CINⅠapparently higher than in cervical carcinoma(P＜0.05). With the clinical stage increased, the positive expression rate of E-cadherin decreased. By comparison of different degree of differentiation, the positive rate was lower with the poorer differentiation of the cancer cells. Besides, the positive expression rate in the cervical carcinoma with lymph node metastasis was apparently higher than without(P＜0.01). For the age factor, it had no correlation with the expression(P＞0.05).④The expression of p16 showed a increasing trend in turn in normal cervical tissues, CINⅠ, CINⅡ～Ⅲand cervical carcinoma. The positive expression rate in normal cervical tissues was apparently lower than in CINⅠ(P＜0.05), and in CINⅠwas apparently lower than in cervical carcinoma(P＜0.05). There was no significant difference within each of the groups of age, FIGO staging and lymph node metastasis(P＞0.05). In the cervical carcinoma with different degree of differentiation, the poorer the degree was, the higher the positive expression rate of p16 was.⑤The positive expression rate of ILK, HIF-1αand p16 had negative correlation with that of E-cadherin.Conclusion:①As a better cell proliferation marker, ILK has certain reference value for the discrimination of normal cervical epithelium, CIN at all levels and cervical carcinoma. But whether it has correlation with the biological behaviour and the degree of malignancy of cervical carcinoma, and whether it helps clinical assessment of prognosis of patients with cervical cancer, needs to further research and follow-up.②The detection and research of HIF-1αwould contribute to early and differential diagnosis of cervical carcinoma, and predict the development trend and metastatic potential of tumors. It is expected to be a new clinical diagnostic criteria and tumor marker. HIF-la/E-cadherin pathway also exists in cervical carcinoma, and further research on the expression and regulation mechanism of HIF-1α/E-cadherin will provide important clues to the diagnosis and treatment of cervical carcinoma.③Abnormal expression of E-cadherin has a hand in the occurrence of cervical carcinoma. Reduced expression of E-cadherin in cervical carcinoma correlates with the over expression of ILK, HIF-1α, p16 and such signaling molecules. This shows that a variety of signaling molecules together with E-cadherin play a part in malignant transformation of cell during the cancerization of cervix. To detect the expression of various signaling molecules together with E-cadherin makes sense to understand the occurrence and development mechanism of cervical carcinoma.④The expression of p16 in cervical carcinoma is apparently higher than that in normal cervical mucosa. And it changes early in the tumor, so it is an early event. To regard detection of p16 as a secondary screening for precancerous lesions of uterine cervix, would help us to judge CIN, to reduce the rate of misdiagnosis of cervical cancer, and so to take early and timely treatment.更多还原