Overexpression of MMP21 and MMP28 is associated with gastric cancer progression and poor prognosis

Abstract

Matrix metalloproteinase (MMP)-21 and MMP-28, or epilysin, are overexpressed during the invasion and metastasis of solid tumors. The present study investigated MMP-21 and MMP-28 expression levels in human gastric cancer using tissue microarray (TMA) analysis, and determined their association with clinicopathological characteristics and patient prognosis. TMA blocks, including 436 cases of gastric cancer and 92 non-cancerous adjacent gastric tissues, were investigated using immunohistochemistry. Staining results were analyzed statistically in association with various clinicopathological characteristics and overall survival. The MMP-21 and MMP-28 positive detection rate was 31.9% (139/436) and 34.4% (150/436), respectively, in the gastric carcinoma tissue specimens. MMP-21 and MMP-28 expression levels were negative in the 92 normal gastric tissue samples. In patients with gastric cancer, positive expression of MMP-21 and MMP-28 was correlated with tumor diameter, depth of invasion, vessel invasion, lymph node and distant metastases and tumor-node-metastasis stage. The overall survival rate was significantly lower in MMP-21 and MMP-28-positive compared with negative patients. Cox multivariate analysis revealed that MMP-21 and MMP-28 levels were independent predictors of survival in patients with gastric cancer. These findings emphasize the importance of MMP-21 and MMP-28, which may serve as novel and independent prognostic markers for the invasion and metastasis of human gastric cancer.

Keywords: cancer progression; gastric cancer; matrix metalloproteinase-21; matrix metalloproteinase-28; prognosis; tissue microarray.

Figure 1.

Immunohistochemical analysis of MMP-21 protein expression levels in gastric cancer tissue and non-cancerous human gastric mucosa using tissue microarray analysis. (A) MMP-21 staining in moderately differentiated adenocarcinoma (magnification, ×40). (B) Magnified image (magnification, ×200) of the area indicated by black arrow in the previous image. Immunostaining of MMP-21 produced yellow-brown granules, primarily in the cytoplasm. (C) MMP-21 staining in poorly differentiated adenocarcinoma (magnification, ×40). (D) Magnified image (magnification, ×200) of the area indicated by black arrow in the previous image. Immunostaining of MMP-21 produced yellow-brown granules, primarily in the cytoplasm. (E) MMP-21 staining in non-cancerous human gastric mucosa (magnification, 40×). Negative staining was observed in normal gastric epithelial cells and a positive signal, considered as nonspecific staining, was detected in gastric basal cells. (F) Magnified image (magnification, ×200) of the area indicated by black arrow in the previous image. The red arrow indicates negative staining in normal gastric epithelial cells. MMP, matrix metalloproteinase.

Figure 2.

Immunohistochemical analysis of MMP-28 expression in gastric cancer tissue and non-cancerous human gastric mucosa using tissue microarray analysis. (A) MMP-28 staining in poorly differentiated adenocarcinoma (magnification, ×40). (B) Magnified image (magnification, ×200) of the area indicated by black arrow in the previous image. Immunostaining of MMP-28 produced yellow-brown granules, primarily in the cytoplasm. (C) MMP-28 staining in moderately differentiated adenocarcinoma (magnification, ×40). (D) Magnified image (magnification, ×200) of the area indicated by black arrow in the previous image. Immunostaining of MMP-28 produced yellow-brown granules, primarily in the cytoplasm. (E) MMP-28 staining in non-cancerous human gastric mucosa (magnification, ×40). Negative staining was observed in normal gastric epithelial cells and a positive signal, considered as nonspecific staining, was detected in gastric basal cells. (F) Magnified image (magnification, ×200) of the area indicated by black arrow in the previous image. The red arrow indicates negative staining in the cytoplasm of normal gastric epithelial cells. MMP, matrix metalloproteinase.

Figure 3.

Kaplan-Meier 5-year survival curves for patients with gastric tumors based on their MMP-21 and MMP-28 expression status. (A) Survival curve for MMP-21-positive and MMP-21-negative patients with gastric cancer. The 5-year survival rate of MMP-21-positive patients was significantly lower compared with that of MMP-21-negative patients. (B) Survival curve for MMP-28-positive and MMP-28-negative patients with gastric cancer. The 5-year survival rate of MMP-28-positive patients was significantly lower compared with that of MMP-28-negative patients. (C) Survival curve for patients with gastric cancer that were positive or negative for MMP-21 and MMP-28. The 5-year survival rate of MMP-28- and MMP-21-positive patients was significantly lower compared with that of MMP-28- and MMP-21 negative patients. MMP, matrix metalloproteinase.