子宫颈癌中HPV16/18感染与MMP-2、9及其抑制因子表达的关系

HPV 16/18 infection and its correlation with matrix metalloproteinase-2,9 and their inhibitor-1,2 in human cervical carcinoma

目的探讨人乳头状瘤病毒HPV16/18在子宫颈癌中的感染情况及与基质金属蛋白酶MMP-2、9及其抑制因子TIMP-1、2表达的关系。方法用原位杂交法检测HPV16/18在57例子宫颈癌(其中子宫颈鳞癌40例、子宫颈腺癌20例、子宫颈腺鳞癌7例),29例宫颈上皮内肿瘤(C IN)和16例正常子宫颈组织中感染情况,采用免疫组织化学方法(SP)检测MMP-2、9蛋白及TIMP-1、2蛋白的表达。结果HPV16/18在子宫颈鳞癌、腺癌、腺鳞癌、C IN和正常子宫颈组织中感染情况分别为67.50%(27/40)、35.00%(7/20)、5/7、68.97%(20/29)、6.25%(1/16)。MMP-2、9及TIMP-1、2在正常宫颈组织细胞浆、C IN、子宫颈鳞癌、腺癌、腺鳞癌中的阳性表达率渐增高,各病变组与正常组相比差异有极显著性(P<0.01);MMP-2鳞癌组的表达较腺癌组高(P=0.006),而MMP-9却相反(P=0.048);TIMP-1在C IN组的表达较鳞癌组高(P=0.042);TIMP-2在病变各组间比差异无统计学意义。HPV16/18感染与MMP-2、9与TIMP-1、2蛋白表达没有相关性;在MMP-2、9与TIMP-1、2间都有正相关。在子宫颈癌的临床病理特征中,HPV感染率没有统计学差异,在淋巴结有转移者中MMP-2、9的表达较未转移者高(P=0.017、0.002),而在TIMP-2中未转移者较有转移者高(P=0.004),但TIMP-1在二者间无统计学差异。结论在子宫颈癌的发生发展中HPV16/18的感染起一定的作用。MMP-2、MMP-9的表达水平的明显上调和TIMP-1、TIMP-2相对弱表达在子宫颈癌浸润和淋巴转移中起了重要的作用。

Objective To investigate the infection of human papillomavirus 16/18 （HPV16/18） and these expressions of matrix metalloproteinase-2, 9 （MMP-2, 9） and their inhibitor-1, 2 （TIMP-1 , 2） in human cervical carcinomas and the relationship among of them. Methods The infection of HPV16/18 DNA in 67 cases of cervical carcinoma （40 cases of squamous-cell carcinoma of the uterine cervix, 20 cases of adenocarcinoma of the uterine cervix, 7 cases of glandular and squamous-cell carcinoma of the uterine cervix） , in 29 cases of cervical intraepithelial neoplasia （CIN） and 16 cases of normal cervices was detected by hybridization in situ. MMP-2, 9 and TIMP-1, 2 were detected by immunohistochemical staining （SP） in these five groups. Results The infection rates of HPV16/18 in squamous-cell carcinoma and adenocarcinoma, glandular and squamous-cell carcinoma of the uterine cervix, CIN and in normal cervical epithelium, were 67.50% （27/40） , 35.00% （7/20） , 5/7, 68. 97% （20/29） , 6. 25% （1/16） respectively. There were significant differences among these cervical lesion groups and the normal cervical epithelium （ P 〈 0. 001 ）. There was significant difference between the squamous-cell carcinoma group and the adenocarcinoma group （ P 〈 0. 001 ） , but no significant difference was found between the squamous-cell carcinoma group and the CIN group. The positive rates of MMP-2, 9 and TIMP-1 , 2 in normal cervical epithelium, CIN, squamous-cell carcinoma, adenocarcinoma, glandular and squamous-cell carcinoma of the uterine cervix increased gradually. There were significant differences between these cervical lesion groups and the control group. MMP-2 expression was higher in squamous cell carcinoma than that in adenocarcinoma of the uterine cervix （ P 〈 0. 001 ） , but MMP-9 expression was lower in squamous cell carcinoma than that in adenocarcinoma of the uterine cervix （P = 0. 048）. The positive rate of TIMP-1 was higher in CIN than that in squamous cell carcinoma of the uterine cervix （P=0. 042）, and no significant differences existed among these cervical lesion groups for TIMP-2. There were no relationships among the infection of HPV16/18 and expressions of MMP-2, 9 or TIMP-1, 2. The positive rates of MMP-2 and MMP-9 in lesion tissues with lymph node metastasis were obviously higher than those without lymph node metastasis （P = 0.017,0.002） ,but the positive rate of TIMP-2 was contrary to those of MMP-2 and MMP-9. There was no significantly difference between TIMP-1 expression in lesion tissues with lymph node metastasis and that without lymph node metastasis. No significant correlation could be established between the infection of HPV16/18 and the expression of MMP-2 or 9 or TIMP- 1 or 2 or the tumor diameter or clinical stage or pathologic grade or pelvic node metastasis. Conclusion The infection of HPV16/18 may play a role in the progress of carcinoma of the uterine cervix. The overexpression of MMP-2, MMP-9, TIMP-1 and TIMP-2 possibly play a key role in invasion and lymph-node metastasis of the human cervical carcinoma.