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Sci Rep. 2018 Jun 22;8(1):9531. doi: 10.1038/s41598-018-27739-w.

PROX1 is a transcriptional regulator of MMP14.

Author information

1
Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
2
Department of Oncology, CHUV and University of Lausanne, Switzerland and Ludwig Institute for Cancer Research, Lausanne, Switzerland.
3
Department of Immunology, Genetics and Pathology, Rüdbeck Laboratory, Uppsala University, Uppsala, Sweden.
4
Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki, Finland.
5
Chelsea and Westminster Hospital and Imperial College London, London, UK.
6
Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
7
Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
8
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
9
Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland. p.ojala@imperial.ac.
10
Section of Virology, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, UK. p.ojala@imperial.ac.
11
Foundation for the Finnish Cancer Institute, Helsinki, Finland. p.ojala@imperial.ac.

Abstract

The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.

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