Prognostic Significance of Ets-1 and the Matrix Metalloproteinase-2 to Tissue Inhibitor of Matrix Metalloproteinase-2 Ratio in Egyptian Epithelial Ovarian Cancer Patients
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The invasive potential of epithelial ovarian cancer is the main factor determining its biological behavior. Ets-1 transcription factor is involved in the activation of several proteases participating in tumor invasion and metastasis. The balance of matrix metalloproteinase-2 and its inhibitor is important in the regulation of tumor invasion. This study included 31 twnors from patients with epithelial ovarian cancer in different stages, and 20 tissue samples from benign ovarian lesions as a control group. Ets-1 was assessed using immunohistochemistry. Matrix metalloproteinase-2 (MMP-2) and the MMP-2 inhibitor (T1MP-2) were measured in the cytosolic fractions using enzyme immunoassay. MMP-2 results were confirmed by gelatin zymography. ETS-1 was expressed only in the malignant group. MMP-2 and the MMP-2:TIMP-2 ratio were significantly higher in the malignant group (p =0045 and a026, respectively) with significant correlation to stage and poor survival above the specified cut-off values (p=0.006 and 0.002, respectively). Log rank of Kaplan-Meier survival analysis was significant for FIGO stage, MMP-2 and the MMP-2:T1MP-2 ratio (p <0.05). Multivariate analysis demonstrated that the MMP-2:TIMP-2 ratio is an independent prognostic parameter. Ets-1 could be a future target for therapeutic strategies. Moreover, the MMP-2:TIMP-2 ratio might serve as a new independent prognostic indicator of poor prognosis in epithelial ovarian cancer patients. The invasive potential of epithelial ovarian tumors is the main factor determining their biological behavior. Despite Correspondence to: Dr. Samar K. Kassim, Medical Biochemistry Department, Faculty of Medicine, AM Shams University, Abbassia, Cairo, Egypt, 11381. Tel: 002 02 6858940, Fax: 002 02 6859928, email: firstname.lastname@example.org Key Words.: Ets-1, MMP-2, T1MP-2, MMP-2:TIMP-2 ratio, ovarian cancer. the inclusion of new chemotherapeutic regimens, the mortality rate from ovarian cancer has remained largely unchanged (1). The Ets-1 proto-oncogene is a transcriptional factor involved in various cellular functions, including activation of several proteases participating in tumor invasion and metastasis as matrix metalloproteinases (2). Matrix metalloproteinases (MMPs) are a group of highly homologous enzymes that can degrade the extracellular matrix proteins and show regulatory changes in neoplasia (3). Type-IV collagenases, the 72-kDa MMP-2 and the 92- kDa MMP-9 degrade the type-IV collagen of the basement membrane, gelatin and fibronectin (4). MMP-2 is secreted as an inactive 72 kDa proenzyme and its activation results from the cleavage of 80 amino acids at the N-terminus with several potential mechanisms operating in vivo, including autocatalytic removal (3) and Ets-1 (2). The resultant active form is 62 kDa. Decreasing type-IV collagenase activity by transfection of tumor cells with tissue inhibitor for matrix metalloproteinas (TIMP) reduces metastatic capacity (5). T1MP-2 specifically inhibits the protease activity of MMP-2. The balance between MM? and TIMP is crucial in the process of tumor invasion and metastasis (6). In view of the importance of this finding and the absence of relevant reports, we examined the relationship between tissue MMP-2:TIMP-2 ratio and prognosis of epithelial ovarian cancer. Moreover, as a possible MMP-2 activator, Ets-1 expression in both benign and malignant ovarian tissues was also addressed. Patients and Methods This study was conducted in the period from May 2000 — June 2003. The clinical specimens were obtained from the Obstetrics and Gynecology Department, Mn Shams University Hospitals, Cairo, Egypt. The laboratory work was carried out at the Oncology Diagnostic Unit (ODU), Medical Biochemistry Department, Ain Shams Faculty of Medicine, Cairo, Egypt.