Association of matrilysin-2 (MMP-26) expression with tumor progression and activation of MMP-9 in esophageal squamous cell carcinoma

• Published in: Carcinogenesis (New York) 2004-12, Vol.25 (12), p.2353-2360
• Main Authors: Yamamoto, Hiroyuki, Vinitketkumnuen, Akravit, Adachi, Yasushi, Taniguchi, Hiroaki, Hirata, Tamaki, Miyamoto, Nobuki, Nosho, Katsuhiko, Imsumran, Arisa, Fujita, Masahiro, Hosokawa, Masao, Hinoda, Yuji, Imai, Kohzoh
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; beta Catenin; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Nucleus - metabolism; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Disease Progression; ECM; Enzyme Activation; ESCC; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; esophageal squamous cell carcinoma; extracellular matrix; Female; Gene Expression Regulation, Neoplastic - physiology; Humans; Immunoenzyme Techniques; Lymphatic Metastasis - pathology; Male; matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinases - genetics; Matrix Metalloproteinases - metabolism; Matrix Metalloproteinases, Secreted; Medical sciences; Middle Aged; MMP; Neoplasm Invasiveness - pathology; Neoplasm Recurrence, Local - pathology; pathological tumor node metastasis; PBS; phosphate-buffered saline; Prognosis; pTNM; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; RT–PCR; Survival Rate; T cell factor; TCF; Trans-Activators - genetics; Trans-Activators - metabolism; Transfection; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgh270

Expression of matrilysin-2, matrix metalloproteinase (MMP)-26, has been implicated in the progression of several types of human cancer. Matrilysin-2 has been reported to be a physiological and pathological activator of pro-MMP-9. The aim of this study was to examine matrilysin-2 expression and determine whether it is correlated with progression of human esophageal squamous cell carcinoma (ESCC). Semi-quantitative reverse transcriptase–polymerase chain reaction, immunohistochemical analysis, zymography and an in vitro invasion assay were performed. Matrilysin-2 mRNA expression was undetectable or only faintly detected in non-tumor tissues, but its overexpression was detected in 24 of the 50 ESCC tissues. Matrilysin-2 overexpression was significantly correlated with depth of invasion, lymph node metastasis and an advance in pathological tumor node metastasis (pTNM) stage. Sections with immunostaining signals in >10% of carcinoma cells at the invasive front, which were observed in 46 of 100 cases, were judged to be positive for matrilysin-2 expression. Matrilysin-2 expression was significantly correlated with depth of invasion, lymph node and distant metastasis, advance in pTNM stage and recurrence. Expression of matrilysin-2 was significantly correlated with nuclear β-catenin expression and MMP-9 expression. Patients with matrilysin-2-positive cancer had significantly shorter overall and disease-free survival periods than did those with matrilysin-2-negative cancer. Matrilysin-2 expression retained its significant predictive value for overall and disease-free survival in multivariate analysis. Moreover, patients with concomitant expression of matrilysin-2 and MMP-9 had the worst prognosis. Zymography revealed that matrilysin-2 expression was significantly correlated with expression of active MMP-9 in ESCC tissues. Matrilysin-2-transfected TE-1 ESCC cells showed active MMP-9 activity and were more invasive in vitro compared with mock-transfected TE-1 cells. The results of this study suggest that matrilysin-2, the expression of which is closely correlated with nuclear β-catenin expression and active MMP-9 activity, plays a key role in the progression of ESCC.