Matrix Metalloproteinase-2 (MMP-2) and its Tissue Inhibitor (TIMP-2) are Prognostic Factors in Cervical Cancer, Related to Invasive Disease but not to High-risk Human Papillomavirus (HPV) or Virus Persistence after Treatment of CIN

Abstract

Objective: 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. Materials and Methods: 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. Results: 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. Conclusion: 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.