Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis

Abstract

The expression of matrix metalloproteinase-2 (MMP-2) has been linked with tumor invasion, angiogenesis, and metastasis. However, the molecular basis for MMP-2 overexpression in tumor cells remains unclear. In this study, by using K-1735 melanoma system, we demonstrated that highly metastatic C4, M2, and X21 tumor cells express elevated MMP-2 mRNA and enzymatic activity, whereas poorly metastatic C10, C19, and C23 tumor cells express much lower levels. Moreover, a concomitant elevated Stat3 activity has been detected in these metastatic tumor cells that overexpress MMP-2. Transfection of constitutively activated Stat3 into poorly metastatic C23 tumor cells directly activated the MMP-2 promoter, whereas the expression of a dominant-negative Stat3 in highly metastatic C4 tumor cells inhibited the MMP-2 promoter. A high-affinity Stat3-binding element was identified in the MMP-2 promoter and Stat3 protein bound directly to the MMP-2 promoter. Blockade of activated Stat3 through expression of a dominant-negative Stat3 significantly suppressed MMP-2 expression in the metastatic tumor cells. Therefore, overexpression of MMP-2 in the metastatic melanoma cells can be attributed to elevated Stat3 activity, and Stat3 upregulates the transcription of MMP-2 through direct interaction with the MMP-2 promoter. Furthermore, blockade of activated Stat3 in highly metastatic C4 cells significantly suppressed the invasiveness of the tumor cells, inhibited tumor growth, and prevented metastasis in nude mice. Collectively, these studies suggest that Stat3 signaling directly regulates MMP-2 expression, tumor invasion, and metastasis, and that Stat3 activation might be a crucial event in the development of metastasis.

Celecoxib induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation

“…Additionally, STAT3 may inhibit apoptosis via the upregulation of Bcl-2, Survivin and Mcl-1 [28][29][30] . STAT3 may also promote cancer cell invasion and metastasis through the induction of matrix metalloprateinase-2 (MMP-2) [31] and increase angiogenesis via the induction of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1α) [32] . Increasing evidence has shown that the inhibition of constitutively activated STAT3 could lead to cancer cell death and tumor regression [33][34][35] .…”

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

“…4A). 41 Because nEGFR interacts with STAT3 in the promoters of their target genes, 22 we investigated the role of STAT3 in the nEGFR-mediated activation of the MMP2 promoter. In H1975 cells, STAT3 knockdown by 2 different shRNA sequences significantly reduced MMP2 mRNA expression (Fig.…”

Genome-wide analysis of STAT target genes: Elucidating the mechanism of STAT-mediated oncogenesis

“…Furthermore, a recent report suggests that STAT3 may contribute to cancer by allowing tumors to evade detection by the host immune system. 36 Finally, STAT3 promotes the motility of ovarian carcinoma cells and the invasiveness of melanoma cells in vitro, 37,38 suggesting that STAT3 may play an important role in regulating these aspects of tumorigenesis in vivo, as well.…”

“…19,28,42,[46][47][48][49] The pro-angiogenic effects of STAT3 are likely to be mediated through upregulation of VEGF. 34,35 STAT3 regulation of matrix metalloproteinase-2 (mmp-2) correlates with invasiveness of melanoma cells, 38 and activation of mmp-9 is required for STAT3-induced transformation of mammary epithelial cells. 50 Thus STAT3 and STAT5 contribute to cancer by activating genes that promote cell cycle entry and cell survival, among other cellular processes (Fig.…”