Abstract
Expression of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), which correlates with tumor invasion and metastasis, has been known to be regulated by several intracellular signaling pathways. Since the CD9 membrane protein has been implicated in signal transduction and malignant progression of cancer cells, we examined the functional involvement of CD9 in the regulation of MMP-2 and MMP-9 expression by using stable CD9 transfectant clones of MelJuso human melanoma cells. The CD9 cDNA-transfected cells with elevated CD9 expression displayed increased MMP-2 and decreased MMP-9 expression when compared with the mock transfectant cells. Among several signal pathway inhibitors tested, SB203580 and SP600125, which inhibit p38 MAPK and JNK respectively, completely blocked the CD9-stimulated MMP-2 expression. Phosphorylation levels of p38 MAPK and c-Jun in MelJuso cells were also significantly increased by CD9 transfection. In addition, the down-regulation of p38 MAPK and JNK by siRNA transfection resulted in a decrease in MMP-2 expression by MelJuso cells. Promoter analysis and gel shift assay showed that the CD9-induced MMP-2 expression is mediated by a functional AP-1 site through interactions with AP-1 transcription factors including c-Jun. These results suggest that CD9 induces MMP-2 expression by activating c- Jun through p38 MAPK and JNK signaling pathways in human melanoma cells.
Highlights
The matrix metalloproteinases (MMPs), which are involved in the degradation of extracellular matrix (ECM), play a role in many physiological processes such as embryonic development, angiogenesis, ovulation, and repair of tissues
Prom oter analysis and gel shift assay showed that the CD9-induced MMP-2 expression is m ediated by a functional activating protein 1 (AP-1) site through interactions with AP-1 transcription factors including c-Jun. These results suggest that CD9 induces MMP-2 expression by activating cJun through p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways in hum an m elanom a cells
Some of the cellular proto-oncogenes have been shown to regulate the expression of MMPs; for example, transfection of MCF-10A breast cancer cells with c-erbB-2 or c-ras led to increased production of MMP-2, whereas transfection of MCF-7 breast cancer cells with ets gene, PEA-3, resulted in increased expression of MMP-9 (Giunciuglio et al, 1995; Kaya et al, 1996)
Summary
The matrix metalloproteinases (MMPs), which are involved in the degradation of extracellular matrix (ECM), play a role in many physiological processes such as embryonic development, angiogenesis, ovulation, and repair of tissues. Increases in activity and expression of MMP-2 and/or MMP-9 have been frequently observed in many human cancers with invasive and metastatic capability (Bernhard et al, 1994; Heppner et al, 1996; Basset et al, 1997; Johnsen et al, 1998). Expression of both MMP-2 and MMP-9 is induced by growth factors, cytokines, phorbol esters, and other environmental factors such as binding to the extracellular matrix (ECM) (Segain et al, 1996; Sehgal et al, 1996; Basset et al, 1997; Kondapaka et al, 1997; Johnsen et al, 1998; Westermarck and Kahari, 1999). We investigated the activity and expression of type IV collagenases in melanoma cells after transfection with CD9 cDNA, because most of the CD9-related biological processes including tumor metastasis are known to be regulated by the MMPs, MMP-2 and MMP-9. Our results indicate that high CD9 expression in melanoma cells results in increased expression of MMP-2 through p38 MAPK- and JNK-dependent AP-1 activation, in contrast to its effect on MMP-9 expression
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