Expression of the Matrix Metalloproteinase-2/9 and Tissue Inhibitor of Metalloproteinase-2 Proteins with Heterozygosity of p53 Gene in Thyroid Tumors

Kim, Seok Beom; Rho, Young Soo; Ahn, Hwoe Young; Cho, Seong Jin; Shin, Hyung Sik

Abstract

BACKGROUND AND OBJECTIVES
Mutations or overexpression of the p53 gene is believed to play an important role in the progression of various human malignant tumors. The type IV collagenase (matrix metalloproteinase: MMP) initiates the degradation of the extracellular matrix and consequently may play a role in the process of tumor invasion and metastasis. Although MMPs are known to be expressed in a variety of tissues and molecular studies in malignant tumor have shown the high frequency of loss of heterozygosity (LOH) in some specific regions, the study on the MMPs expression along with LOH on p53 gene related to clinicopathological parameters in thyroid tumors is very rare. MATERIALS AND METHOD: In this study, we examined the MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP) -2 expression in association with p53 gene LOH using immunohistochemical method and molecular polymorphic analysis in 100 cases of thyroid tumors (50 papillary carcinomas, 10 follicular carcinomas, 20 follicular adenomas, 20 nodular hyperplasias). LOH was examined at four p53 gene related microsatellite loci including TP53, D17S796, D17S5, D17S513. RESULTS: By immunohistochemistry, MMP-2 expression was detected in 37 (74%) papillary carcinomas, 4 (40%) follicular carcinomas, 5 (25%) follicular adenomas and 2 (10%) nodular hyperplasia cases. MMP-9 expression was detected in 35 (70%) papillary carcinomas, 4 (40%) follicular carcinomas, 4 (20%) follicular adenomas and 2 (10%) nodular hyperplasia cases. TIMP-2 expression was detected in 32 (64%) papillary carcinomas, 4 (40%) follicular carcinomas, 4 (20%) follicular adenomas and 1 (5%) nodular hyperplasia cases. By PCR-polymorphism study, p53 LOH was detected in 31 (62%) papillary carcinomas, 8 (80%) follicular carcinomas, 6 (30%) follicular adenomas and 0 (0%) nodular hyperplasia cases. The differences in MMP-2, MMP-9 and TIMP-2 expression rates and p53 LOH between malignant and benign tumors were statistically significant. Also, MMP-2, MMP-9, TIMP-2 expression and p53 LOH correlated well with higher tumor histologic grade. Also statistically significant correlation was found between p53 LOH and lymph node metastasis. The MMP-2 expression showed increased tendency of lymphatic emboli formation and lymph node metastasis, but there was not statistically significant. MMP-2 expression was well correlated with MMP-9 expression and p53 LOH, but there is no remarkable correlation of expression of MMP-2 and MMP-9 comparable to TIMP-2 expression. CONCLUSION: We concluded that the expression of MMP-2, MMP-9 and TIMP-2 with p53 LOH may contribute to the malignant transformation and poorly differentiated grade in thyroid tumors. Also, MMP-2 expression may be regulated by p53 gene.