Cryptic collagen IV promotes cell migration and adhesion in myeloid leukemia.
Bottom Line: Exposure to denatured collagen IV significantly increased the migration and adhesion of K562 cells, which also resulted in increased activation of DDR1 and AKT.Importantly, BM samples of AML patients exhibited increased levels of remodeled collagen IV compared to native as analyzed via anti-HUIV26 antibody.Further understanding of this phenomenon may lead to the development of therapeutic agents that directly modulate the BM microenvironment and attenuate leukemogenesis.
Affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, 04074, Maine; The Graduate School of Biomedical Science and Engineering, University of Maine, Orono, 04469, Maine.Show MeSH
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Mentions: Analysis of secreted matrix metalloproteinases 9 (MMP-9) in the CM via western blot from K562 cells exposed to either native or denatured collagen IV showed increased levels of MMP-9 with denatured collagen IV (Fig. 2A). Interestingly, MMP-9 dependent exposure of the HUIV26 cryptic site on collagen IV has been showed to promote endothelial cell migration and neovascularization 13. Currently, these outcomes suggest a possible feed forward loop for collagen IV-DDR1-MMP9-cryptic collagen IV in promoting migration and adhesion of leukemic cells. Further, liquid chromatography/tandem mass spectrometry (LC/MS/MS) QSTAR proteomic analysis of CM revealed exclusive presence of Secretogranin 3 (SCG3/SGIII) and InaD-like protein (INADL/PATJ) in the denatured collagen IV CM (Fig. 2B–C) in addition to several other interesting factors (top ones shown in Table S1). INADL/PATJ is a multiple PDZ domain containing protein known to localize to tight junctions or apical membranes and is predicted to regulate cell polarity 14. SCG3/SGIII belongs to the granin family and is known to regulate secretory pathways of peptides, hormones, neurotransmitters, and growth factors in the transgolgi-network 15. These novel cryptic collagen IV-induced factors in the CM of leukemic cells may play supportive roles in promoting migration and adhesion in BM niche.
Affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, 04074, Maine; The Graduate School of Biomedical Science and Engineering, University of Maine, Orono, 04469, Maine.