拓扑异构酶IIα的过表达与宫颈上皮内瘤变（CIN）的分级及高危型人乳头瘤病毒（HPV）相关，但不能预测宫颈癌的预后或锥形切除术后HPV的清除情况。

Over-expression of topoisomerase IIalpha is related to the grade of cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus (HPV), but does not predict prognosis in cervical cancer or HPV clearance after cone treatment.

作者信息

Branca Margherita, Giorgi Colomba, Ciotti Marco, Santini Donatella, Di Bonito Luigi, Costa Silvano, Benedetto Arrigo, Bonifacio Daniela, Di Bonito Paola, Paba Pierpaulo, Accardi Luisa, Mariani Luciano, Ruutu Merja, Syrjänen Stina M, Favalli Cartesio, Syrjänen K

机构信息

Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità, ISS, Rome, Italy.

出版信息

Int J Gynecol Pathol. 2006 Oct;25(4):383-92. doi: 10.1097/01.pgp.0000209573.54457.32.

DOI:10.1097/01.pgp.0000209573.54457.32

PMID:16990717

Abstract

OBJECTIVE

One of the pathways leading to cervical cancer is a loss of normal cell cycle control. Topoisomerase IIalpha and IIbeta are important nuclear proteins controlling the G2/M checkpoint, and shown to be over-expressed in many human cancers. Their links to oncogenic human papillomavirus (HPV) types and their prognostic value in cervical cancer are practically unexplored.

MATERIAL AND METHODS

As part of our HPV-PathogenISS study, a series of 150 squamous cell carcinomas (SCC) and 152 CIN lesions were examined using immunohistochemical (IHC) staining for topoisomerase IIalpha (topo IIalpha), and tested for HPV using PCR with three primer sets (MY09/11, GP5/GP6, SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV clearance/persistence after cone treatment.

RESULTS

Topo IIalpha expression increased with increasing grade of CIN (p = 0.0001), with the most dramatic up-regulation upon progression from CIN2 to CIN3 and peaking in SCC (OR 16.23; 95%CI 7.89-33.38). Topo IIalpha up-regulation was also significantly associated with HR-HPV detection in univariate analysis (OR = 3.07; 95%CI 1.70-5.52), but was confounded by the histological grade (Mantel-Haenszel common OR = 1.622; 95%CI 0.782-3.365), and by entering both p16(INK4a) (9) and Survivin (33) in the multivariate regression model. Topo IIalpha did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic factor in cervical cancer in either univariate or multivariate analysis.

CONCLUSIONS

Over-expression of topo IIalpha is significantly associated with progression from CIN2 to CIN3, being a late marker of cell proliferation. Its close association with HR-HPV is plausibly explained by the fact that E7 oncoproteins of these HR-HPV (but not LR-HPV) block the normal pRb-mediated inhibition of topo IIalpha by degrading the wild-type Rb.

摘要

目的

导致宫颈癌的途径之一是正常细胞周期控制的丧失。拓扑异构酶IIα和IIβ是控制G2/M期检验点的重要核蛋白，且在许多人类癌症中呈过表达。它们与致癌性人乳头瘤病毒（HPV）类型的联系及其在宫颈癌中的预后价值实际上尚未得到探索。

材料与方法

作为我们HPV-PathogenISS研究的一部分，使用拓扑异构酶IIα（拓扑IIα）的免疫组织化学（IHC）染色检查了一系列150例鳞状细胞癌（SCC）和152例CIN病变，并使用三组引物（MY09/11、GP5/GP6、SPF）通过PCR检测HPV。所有SCC患者均有随访数据，67例CIN病变在锥切治疗后通过连续PCR监测HPV清除/持续情况。

结果

拓扑IIα表达随CIN分级增加而升高（p = 0.0001），从CIN2进展到CIN3时上调最为显著，并在SCC中达到峰值（比值比16.23；95%置信区间7.89 - 33.38）。在单变量分析中，拓扑IIα上调也与高危型HPV检测显著相关（比值比 = 3.07；95%置信区间1.70 - 5.52），但受组织学分级影响（Mantel-Haenszel共同比值比 = 1.622；95%置信区间0.782 - 3.365），并且在多变量回归模型中纳入p16(INK4a)（9）和生存素（33）后也受影响。拓扑IIα不能预测CIN治疗后高危型HPV的清除/持续情况，在单变量或多变量分析中它都不是宫颈癌的预后因素。