HER2-dependent MMP-7 expression is mediated by activated STAT3.

MMP-7 expression is highly regulated at the level of transcription. An understanding of how the MMP-7 gene is regulated is critical to elucidate the mechanisms of MMP-7 overexpression in the early tumor development. In the present study, increased mRNA and protein expressions of MMP-7 were observed in MCF-7 cells stably overexpressing HER2 (MCF-7/HER2). The promoter activity of MMP-7 gene was upregulated in MCF-7/HER2 cells and significantly enhanced by HRG induction. Examination of the MMP-7 promoter sequence revealed three potential STAT3 binding sites within the proximal region. MMP-7 promoter activity was remarkably induced in MCF-7 cells expressing the constitutively activated STAT3 (MCF-7/STAT3C). RT-PCR and Western blot analysis confirmed the expression upregulation of mRNA and protein of MMP-7 in the MCF-7/STAT3C cells. Binding of STAT3 to MMP-7 promoter was verified by ChIP and the critical STAT3 element within the MMP-7 promoter identified by the mutagenesis of the core STAT3 recognition sequence. Increased STAT3 phosphorylation was observed in either HER2 overexpressing cells or HRG-induced cells. The data indicate that HRG-induced HER2-dependent transcriptional upregulation and protein secretion of MMP-7 are mediated by activated STAT3. The expression of MMP-7 may be attributed to HER2/STAT3 activation.