Abstract
EMMPRIN (extracellular matrix metalloproteinase inducer, EMN, CD147) is a member of the immunoglobulin superfamily expressed in numerous cell types both as a soluble and a membrane-spanning glycoprotein. It is involved in many physiological processes, as well as in cancer. This study addresses mechanisms of crosstalk between EMN-driven cancer-related cellular responses and the canonical Wnt-pathway in MCF-7 breast carcinoma cells. Genetic knockdown of EMN in MCF-7 resulted in characteristic changes in cellular shape, organization of the actin cytoskeleton and malignancy profile, indicating that EMN expression represses cell motility, but, in contrast, exerts a stimulatory effect on cell proliferation and invasive properties. Increased invasiveness coincided with elevated expression of Wnt-target genes and established invasion driver matrix metalloproteinase MMP14. Activation of the downstream Wnt-pathway by means of heterologous β-catenin and/or TCF-4 expression, through inhibition of GSK-3β by LiCl treatment, or by cell stimulation with insulin-like growth factor-1 (IGF-1) resulted in increased EMN expression. EMN over-expression raised the ratio of the two opposing Wnt pathway-driven transcription factors Sp1 and Sp5, leading to stimulation of the EMN promoter. Furthermore, the EMN promoter was activated by a feed-forward circuit involving an EMN-dependent drop in expression of the repressive signal transducer and activator of transcription 1 (STAT1). Taken together, we show that the influence of EMMPRIN on malignancy-related properties of breast cancer cells is functionally connected to both Wnt- and JAK/STAT pathways.
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Acknowledgements
This work was supported by the Thüringer Aufbaubank (European Regional Development Fund Grants FE 9034 and FE 9053) and the Interdisziplinäres Zentrum für klinische Forschung (IZKF), Jena. We are grateful to Andreas Till for EMN cDNA and the EMN-knockdown constructs, to Oliver Krämer for the STAT1 expression construct and to Sonnhild Mittag for valuable discussions.
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NK performed and documented all experiments, OH designed, supervised and interpreted experiments concerned with Wnt pathway analysis, KF designed and supervised the study and wrote the manuscript.
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Knutti, N., Huber, O. & Friedrich, K. CD147 (EMMPRIN) controls malignant properties of breast cancer cells by interdependent signaling of Wnt and JAK/STAT pathways. Mol Cell Biochem 451, 197–209 (2019). https://doi.org/10.1007/s11010-018-3406-9
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DOI: https://doi.org/10.1007/s11010-018-3406-9