CYR61 Downregulation Correlates with Tumor Progression by Promoting MMP-7 Expression in Human Gastric Carcinoma

Abstract

Objective: CYR61 (cysteine-rich 61) belongs to the CCN (CYR61/CTGF/NOV) protein family and is involved in tumorigenesis. We have previously confirmed that the level of CYR61 protein is decreased in gastric carcinoma compared with nontumoral mucosa, by conducting proteome-based analyses. In this study, we examine the relationship between CYR61 expression and clinicopathological data of MMP-7 expression in human gastric mucosae and tumors. Methods: Immunohistochemical and/or immunofluorescence analyses were performed to examine the histological expression of CYR61 in normal gastric mucosa, intestinal metaplasia, 33 adenomas, and 127 carcinomas. Seven gastric carcinoma cell lines were used to examine the expression of CYR61 and MMP-7 by Western blotting. Results: The CYR61-expressing cells mostly coincided with the serotonin-containing cells, not only in nontumoral epithelia, but also among tumor cells. CYR61 expression was positive (labeling index: >2%) in 43 of 49 early gastric carcinomas (87.8%) and in 19 of 78 advanced gastric carcinomas (24.4%), the frequency being significantly lower in the latter (p < 0.001). All the normal mucosae, intestinal metaplasias and adenomas were in the positive group. The reduction in CYR61 expression correlated significantly with histological differentiation (p < 0.05), depth of invasion (p < 0.001), lymphatic invasion (p < 0.001), venous invasion (p < 0.001), lymph node metastasis (p < 0.001) and clinical stage (p < 0.001). Immunohistochemistry and Western blotting revealed the expression of CYR61 to be inversely correlated with that of MMP-7 (p < 0.001). Conclusions: CYR61 is expressed in serotonin-containing cells, and downregulation of the expression might contribute to the progression of cancer by promoting MMP-7 expression in human gastric carcinomas.