MT3-MMP down-regulation promotes tumorigenesis and correlates to poor prognosis in esophageal squamous cell carcinoma

Abstract

The membrane-type matrix metalloproteinases (MT-MMPs) play an important role in degrading the extracellular matrix (ECM) and facilitating protease-dependent tumor progression and invasion. Here, we report that unlike MT1-MMP, MT3-MMP was down-regulated in esophageal squamous cell carcinoma (ESCC) as detected by real-time PCR (qPCR), Western blot analysis, and immunohistochemistry (IHC). Down-regulation of MT3-MMP was observed at protein level in 66.3% of ESCC specimens (by IHC, n = 86) for routine pathologic diagnosis, as well as at mRNA level in 63.3% of surgically resected ESCC tumors paired with surrounding nontumor tissues (by qPCR, n = 30). Notably, MT3-MMP down-regulation significantly correlated with lymph node metastasis and poor overall survival of patients with ESCC (median 5-year survival = 50.69 vs. 30.77 months for patients with MT3-MMP-negative and -positive ESCC, respectively). Mechanistically, MT3-MMP negatively regulated proliferation, colony formation, and migration of ESCC cells, in association with cell cycle arrest at G1, due to up-regulation of p21^Cip1 and p27^Kip1. Together, as a tumor suppressor in ESCC, MT3-MMP down-regulation represents an unfavorable factor for prognosis of patients with ESCC.

Collectively, our observations provide first evidence for a notion that MT3-MMP acts like a tumor suppressor to negatively regulate tumor progression and aggressiveness of esophageal squamous cell carcinoma (ESCC), and also raise the possibility that MT3-MMP down-regulation may be an independent unfavorable factor for prognosis of patients with ESCC.

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