a concerted hif-1αmt1-mmp signalling axis regulates the expression of the 3bp2 adaptor protein in hypoxic mesenchymal stromal cells共同hif-1αmt1-mmp信号轴调节缺氧的3 bp2适配器蛋白质的表达间充质基质细胞.pdfVIP

A Concerted HIF-1a/MT1-MMP Signalling Axis Regulates the Expression of the 3BP2 Adaptor Protein in Hypoxic Mesenchymal Stromal Cells ´ . . Sebastien Proulx-Bonneau , Amel Guezguez , Borhane Annabi* ´ ´ ´ ´ ` ´ Laboratoire d’Oncologie Moleculaire, Centre de recherche BIOMED, Departement de Chimie, Universite du Quebec a Montreal, Quebec, Canada Abstract Increased plasticity, migratory and immunosuppressive abilities characterize mesenchymal stromal cells (MSC) which enable them to be active participants in the development of hypoxic solid tumours. Our understanding of the oncogenic adaptation of MSC to hypoxia however lacks the identification and characterization of specific biomarkers. In this study, we assessed the hypoxic regulation of 3BP2/SH3BP2 (Abl SH3-binding protein 2), an immune response adaptor/scaffold protein which regulates leukocyte differentiation and motility. Gene silencing of 3BP2 abrogated MSC migration in response to hypoxic cues and generation of MSC stably expressing the transcription factor hypoxia inducible factor 1alpha (HIF-1a) resulted in increased endogenous 3BP2 expression as well as cell migration. Analysis of the 3BP2 promoter sequence revealed only one potential HIF-1a binding site within the human but none in the murine sequence. An alternate early signalling cascade that regulated 3BP2 expression was found to involve membrane type-1 matrix metalloproteinase (MT1- MMP) transcriptional regulation which gene silencing abrogated 3BP2 expression in response to hypoxia. Collectively, we provide evidence for a concerted HIF-1a/MT1-MMP signalling axis that explains th