Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Expression and Its Prognostic Significance in Oral Cancer Patients.

Abstract

Background: Tissue inhibitors of matrix metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs) that inhibit the action of MMPs in 1:1 stoichiometry. TIMP-1 inhibits MMP-9 and MMP-13 and keeps them in an inactive stage. The imbalance between the MMPs and TIMPs disturbs the integrity of the extracellular matrix, which leads to disease progression and metastasis.

Objective: The aim of the present study is to analyze the expression of TIMP-1 in oral cancer patients and compare it with a healthy control. We also analyze the TIMP-1 expression in patients over a two-year follow-up. Moreover, the present study also correlated the TIMP-1 expression with the survival duration, recurrence, and mortality rate. Additionally, predictive accuracy of TIMP-1 for survival outcomes was evaluated.

Methodology: A total 60 subjects enrolled in this study among which 46 were oral cancer patients and 14 were healthy controls. TIMP-1 expression was analyzed in serum samples of healthy controls and patients using the ELISA. Immunohistochemical analysis of IHC was also done for tissue samples of patients. After two years of follow-up, TIMP-1 was again analyzed using ELISA in serum samples of oral cancer patients. TIMP-1 concentration was compared between controls and patients and in patients after two years of follow-up. TIMP-1 expression level was correlated with the overall survival, disease-free survival, mortality, and recurrence rates.

Results: The mean concentration of TIMP-1 was found to be significantly higher in the oral cancer patients (487.4 ± 459.4 ng/ml) as compared to the healthy control (205.1 ± 109.3 ng/ml). TIMP-1 levels were also found to be significantly higher in oral cancer patients after two years of follow-up (487.4 ± 459.4 ng/ml) as compared to the baseline values. The mean TIMP-1 concentration was found to be higher in mortality cases (566.89 ± 493.11 ng/ml) as compared to the survival cases (469.31 ± 465.59 ng/ml); however, the difference was not statistically significant. TIMP-1 concentration exhibits a nonsignificant weak negative correlation with overall survival, whereas it exhibits a nonsignificant but strong negative correlation with disease-free survival. TIMP-1 was found to be 54% accurate in predicting mortality and 38% accurate in predicting the recurrence.

Conclusion: This study underscores the potential of TIMP-1 as a prognostic marker in oral cancer. A high expression of TIMP-1 was found to be correlated with poor treatment outcomes in the patients. A possible reason for this could be an additional intracellular FAK signaling pathway that led to cell proliferation or TIMP-1 may have found to be rise in response to higher MMPs in the cancer cases. Further studies need to investigate the network of interconnected molecular pathways playing a role in disease progression.