Branca M, Ciotti M, Giorgi C, Santini D, Di Bonito L, Costa S, Benedetto A, Bonifacio D, Di Bonito P, Paba P, Accardi L, Syrjänen S, Favalli C, Syrjänen K
Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Rome.
Anticancer Res. 2006 Mar-Apr;26(2B):1543-56.
Matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (TIMP-2) are important regulators of cancer invasion and metastasis. Their associations to high-risk (HR) human papillomavirus (HPV) in cervical intra-epithelial neoplasia (CIN) and cervical cancer (CC) are unexplored and their prognostic significance in CC remains controversial.
As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for MMP-2 and TIMP-2 and tested for HPV using PCR with 3 primer sets (MY09/11, GP5+/GP6+, SPF). Follow-up data were available from all squamous cell carcinoma patients and 67 CIN lesions had been monitored with serial PCR for HPV after cone treatment.
MMP-2 increased with the grade of CIN, with major up-regulation upon transition to invasive cancer (OR 20.78) (95%CI 7.16-60.23) (p=0.0001). TIMP-2 retained its normal expression until CIN3, with dramatic down-regulation in invasive disease (p=0.0001 for trend). Thus, the MMP2:TIMP-2 ratio increased with progressive CIN, exceeding the value 1.0 only in invasive disease. Both MMP-2 and TIMP-2 are highly specific (TIMP-2; 100%) discriminators of CIN with 100% positive predictive value (TIMP-2), but suffer from low sensitivity and negative predictive value. Neither MMP-2 nor TIMP-2 showed any significant association with HR HPV or virus persistence/clearance. TIMP-2 (but not MMP-2) was a significant predictor of survival in univariate (Kaplan-Meier) analysis (p=0.007), but lost its significance in multivariate (Cox) analysis.
The activities of MMP-2 and TIMP-2 in cervical carcinogenesis seem to be unrelated to HR-HPV The inverse MMP-2:TIMP-2 ratio is a sign of poor prognosis. A combination of a TIMP-2 assay with another test showing high SE and high NPV (e.g., HCII for HPV) should provide a potential screening tool capable of accurate detection of CIN.
基质金属蛋白酶-2（MMP-2）及其组织抑制剂（TIMP-2）是癌症侵袭和转移的重要调节因子。它们与宫颈上皮内瘤变（CIN）和宫颈癌（CC）中的高危（HR）人乳头瘤病毒（HPV）的关联尚未得到探索，且它们在CC中的预后意义仍存在争议。
作为我们HPV-PathogenISS研究的一部分，对150例CC和152例CIN病变进行了一系列检测，采用免疫组织化学（IHC）染色检测MMP-2和TIMP-2，并使用3组引物（MY09/11、GP5+/GP6+、SPF）通过PCR检测HPV。所有鳞状细胞癌患者均有随访数据，67例CIN病变在锥形切除术后通过连续PCR监测HPV。
MMP-2随着CIN分级增加，在转变为浸润性癌时出现主要上调（比值比20.78）（95%置信区间7.16 - 60.23）（p = 0.0001）。TIMP-2在CIN3之前保持正常表达，在浸润性疾病中显著下调（趋势p = 0.0001）。因此，MMP2:TIMP-2比值随着CIN进展而增加，仅在浸润性疾病中超过1.0。MMP-2和TIMP-2都是CIN的高度特异性（TIMP-2为100%）鉴别指标，阳性预测值均为100%（TIMP-2），但敏感性和阴性预测值较低。MMP-2和TIMP-2均未显示与HR HPV或病毒持续存在/清除有任何显著关联。在单因素（Kaplan-Meier）分析中，TIMP-2（而非MMP-2）是生存的显著预测指标（p = 0.007），但在多因素（Cox）分析中失去其显著性。
MMP-2和TIMP-2在宫颈癌发生中的活性似乎与HR-HPV无关。MMP-2:TIMP-2比值倒置是预后不良的标志。将TIMP-2检测与另一种显示高敏感性和高阴性预测值的检测方法（如用于HPV的HCII）相结合，应能提供一种能够准确检测CIN的潜在筛查工具。
