نبذة مختصرة : 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. ; Peer reviewed
Relation: We are grateful to Justin Weir (Charing Cross Hospital, and the London Clinic, London) for providing the KS tumour sections, Katri Koli (University of Helsinki) for providing the HepG2 cell line, Thomas F. Schulz (Hannover Medical School, Germany) for providing HuAR2T cell line and to Ralf Adams (Max Planck Institute for Molecular Biomedicine, Muenster) for providing the Cdh5-CreER T2 mice. Mikko Turunen (University of Helsinki) is acknowledged for his help in optimizing the ChIP. We thank also Raquel Diaz Martinez, Lotta Honkala, Nadezhda Zinovkina, Veronika Rezov, Sari Tynkkynen and Jenny Barlund for the technical assistance. We acknowledge the Bioimaging Unit (University of Helsinki) and the Genome-Biology Unit (University of Helsinki) for the technical support in imaging. The study was supported by the Centre of Excellence grant (Translational Cancer Biology; P.M.O., K.A.) and a postdoctoral researcher grant (S.G.) from the Academy of Finland, Finnish Cancer Foundations (P.M.O, K.L.), Sigrid Juselius Foundation (P.M.O.), and University of Helsinki Foundations (P.M.O) and University of Helsinki Foundations (P.M.O). E.K. was supported by the Helsinki Biomedical Graduate Program (HBGP; University of Helsinki). We also acknowledge funding from the Karolinska Institutet (K.L.), the Swiss National Science Foundation (PPP0033-114898 to T.V.P.) and the Swedish Research Council (542-2014-3535 to T.M.).; Gramolelli , S , Cheng , J , Martinez-Corral , I , Vähä-Koskela , M , Elbasani , E , Kaivanto , E , Rantanen , V , Tuohinto , K , Hautaniemi , S , Bower , M , Haglund , C , Alitalo , K , Mäkinen , T , Petrova , T V , Lehti , K & Ojala , P M 2018 , ' PROX1 is a transcriptional regulator of MMP14 ' , Scientific Reports , vol. 8 , 9531 . https://doi.org/10.1038/s41598-018-27739-w; ORCID: /0000-0002-7749-2694/work/46834592; http://hdl.handle.net/10138/237191; f6b6e6fb-082d-41f2-9333-a241275d39b3; 85048952656; 000436046500045
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