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A Significant Elevation of Plasma Level of Matrix Metalloproteinase—9 in Patients With High-Grade Intraepithelial Neoplasia and Early Squamous Cell Carcinoma of the Uterine Cervix

Institute of Medicine Chung Shan Medical University, Taichung, Taiwan, ysf{at}csmu.edu.tw

Po-Hui Wang, MD, PhD

Institute of Medicine Chung Shan Medical University, Taichung, Taiwan, School of Medicine Chung Shan Medical University, Tachung, Taiwan, Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan

Long-Yau Lin, MD, PhD

Institute of Medicine Chung Shan Medical University, Taichung, Taiwan, School of Medicine Chung Shan Medical University, Tachung, Taiwan, Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan

Jiunn-Liang Ko, PhD

Institute of Medical and Molecular Toxicology Chung Shan Medical University. Tachung, Taiwan

Gin-Den Chen, MD

School of Medicine Chung Shan Medical University, Tachung, Taiwan, Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan

Jia-Sin Yang, MS

Institute of Medicine Chung Shan Medical University, Taichung, Taiwan,

Hong-Shen Lee, PhD

Institute of Medicine Chung Shan Medical University, Taichung, Taiwan

Yih-Shou Hsieh, PhD

Institute of Biochemistry and Biotechnology Chung Shan Medical University, Taichung, Taiwan

The objective of this article is to study the correlation between plasma levels of matrix metalloproteinase—2 and —9 (MMP-2 and MMP-9) and multisteps of cervical carcinogenesis as well as to evaluate their clinical application. Two hundred one blood samples were collected from 52 patients with early cervical squamous cell carcinoma (SCC), 41 with high-grade cervical intraepithelial neoplasia (CIN), 27 with low-grade CIN, and 81 healthy individuals. Enzyme-linked immunosorbent assay was used to detect plasma MMP-2 and MMP-9 concentrations. Gelatin zymography was used to directly compare the activities of MMP-2 and MMP-9 and to measure the MMP-9:MMP-2 ratio. A receiver-operating characteristic curve was plotted to determine the plasma cuto f levels of these biomarkers. Patients with low- and high-grade CIN were found to have significantly di ferent plasma MMP-9 levels (P < .001) but not MMP-2 levels. The cuto f values of 103.8 ng/mL for plasma MMP-9 and 0.70 for the MMP-9:MMP-2 ratio were used to distinguish SCC and high-grade CIN from low-grade CIN and healthy cases. The sensitivities and negative predictive values of these cuto f points were high (75.6% and 75.8% for MMP-9; 79.6% and 79.8% for the MMP-9:MMP-2 ratio). A significant elevation of plasma MMP-9 levels and the MMP-9:MMP-2 ratio in high-grade CIN and SCC patients manifests a stage point of high-grade CIN in cervical carcinogenesis and can be used as additional molecular information. Once plasma MMP-9 levels fall below 103.8 ng/mL or the MMP-9:MMP-2 ratio falls below 0.70, patients have only about a 20% chance of developing these cervical lesions.

Key Words: Plasma matrix metalloproteinase-9 • plasma MMP-9:MMP-2 ratio • high-grade cervical intraepithelial neoplasia • squamous cell carcinoma • cutoff level.

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