, Volume 24, Issue 7, pp 541-550

Interaction of MT1-MMP and laminin-5γ2 chain correlates with metastasis and invasiveness in human esophageal squamous cell carcinoma

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Abstract

To gain insights into metastatic mechanisms in esophageal squamous cell carcinoma (ESCC), we established sublines (MLuB1 and MLuC1) with different capacity of spontaneous lung metastasis by subcutaneous injection of a human ESCC cell line (EC 9706) into nude mices. The incidence of the mice with lung metastasis produced by MLuC1 (87%) was significantly higher than that of MLuB1 (22%). The gene expression profiles of the two sublines were compared with cDNA arrays containing 5,000 known genes, and 47 genes were differentially expressed ≥2.0 fold. Laminin-5γ2 chain (Ln-5γ2) was one of the up-regulated genes in MLuC1 cells. Proteolytically processed forms of γ2 are known to promote migration of a multitude of epithelial cells in vitro. Western-blotting analysis revealed that degraded fragments of Ln-5γ2 and active form of membrane-type matrix metalloproteinase-1 (MT1-MMP) in MLuC1 was significantly higher than those in MLuB1. Expression of MT1-MMP was observed in 60 of 75 Ln-5γ2-positive carcinoma tissues (80%). Co-expression of the two proteins was significantly associated with depth of invasion (P = 0.012). Moreover, proteolytic fragments of Ln-5γ2 and active forms of MT1-MMP were frequently found in tumor tissues, whereas in the corresponding normal esophageal tissues there were only intact forms of γ2 and MT1-MMP. siRNA-mediated silencing of MT1-MMP significantly reduced production of γ2′ and γ2x in MLuC1 cells and inhibited cell migration. The results suggest that MT1-MMP is an enzyme responsible for Ln-5γ2 cleavage in ESCC, and interaction between them may play a critical role in promoting invasion and metastasis of human ESCC.