Abstract
Extracellular proteolysis mediates tissue homeostasis. In cancer, altered proteolysis leads to abnormal tumor growth, inflammation, tissue invasion, and metastasis. Matrix metalloproteinase-9 (MMP-9) represents one of the most prominent proteinases associated with inflammation and tumorigenesis. The recently identified human transcription factor sLZIP is a member of the leucine zipper transcription factor family. Although sLZIP is known to function in ligand-induced transactivation of the glucocorticoid receptor, its exact functions and target genes are not known. In this study, we investigated the role of sLZIP in MMP-9 expression and its involvement in cervical cancer development. Our results show that sLZIP increased the expression of MMP-9 at both the mRNA and protein levels and the proteolytic activity of MMP-9 in HeLa and SiHa cells. sLZIP also increased the transcriptional activity of MMP-9 by binding directly to the cAMP-responsive element of the MMP-9 promoter region. Involvement of sLZIP in MMP-9 expression was further supported by the fact that ME-180 cells expressing sLZIP siRNA were refractory to MMP-9 expression. Results from wound healing and invasion assays showed that sLZIP enhanced both the migration and invasion of cervical cancer cells. The increased migration and invasion of HeLa and SiHa cells that were induced by sLZIP were abrogated by inhibition of the proteolytic activity of MMP-9. These results indicate that sLZIP plays a critical role in MMP-9 expression and is probably involved in invasion and metastasis of cervical cancer.
Highlights
Proteolytic degradation of the extracellular matrix and basement membranes by matrix metalloproteinases (MMPs) is crucial in tumor invasion and metastasis
Among different types of MMPs, sLZIP significantly increased the mRNA level of Matrix metalloproteinase-9 (MMP-9) in HeLa cervical cancer cells but not in breast and lung cancer cell lines (Fig. 1A). sLZIP slightly increased the mRNA levels of MMP-9, -10, and -13 in DU-145 prostate cancer cells (Fig. 1A)
SLZIP increased the mRNA levels of MMP-10 and -13 in HeLa cells, we focused on the role of sLZIP in MMP-9 expression in cervical cancer cells because the effect of sLZIP on MMP-9 expression was significant
Summary
Proteolytic degradation of the extracellular matrix and basement membranes by matrix metalloproteinases (MMPs) is crucial in tumor invasion and metastasis. Results: sLZIP induces the expression of MMP-9, leading to enhancement of migration and invasion of cervical cancer cells. The increased migration and invasion of HeLa and SiHa cells that were induced by sLZIP were abrogated by inhibition of the proteolytic activity of MMP-9. These results indicate that sLZIP plays a critical role in MMP-9 expression and is probably involved in invasion and metastasis of cervical cancer. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are capable of degrading ECM proteins and basement membranes at physiological pH values and are involved in a wide range of normal and pathological conditions, including inflammation, tissue repair, tumor invasion, and metastasis (4, 6 – 8). Our results indicate that sLZIP probably contributes to MMP-9-induced tumor progression by enhancing the invasion potential
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