1. The implication of serum HLA-G in angiogenesis of multiple myeloma.
- Author
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Wang C, Su NW, Hsu K, Kao CW, Chang MC, Chang YF, Lim KH, Chiang YH, Chang YC, Sung MT, Wu HH, and Chen CG
- Subjects
- Humans, Animals, Mice, Male, Female, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A blood, Middle Aged, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Aged, Disease Models, Animal, Angiogenesis, Multiple Myeloma blood, Multiple Myeloma metabolism, Multiple Myeloma pathology, Neovascularization, Pathologic metabolism, HLA-G Antigens blood, HLA-G Antigens metabolism, Interleukin-6 blood, Interleukin-6 metabolism
- Abstract
Background: Despite the advances of therapies, multiple myeloma (MM) remains an incurable hematological cancer that most patients experience relapse. Tumor angiogenesis is strongly correlated with cancer relapse. Human leukocyte antigen G (HLA-G) has been known as a molecule to suppress angiogenesis. We aimed to investigate whether soluble HLA-G (sHLA-G) was involved in the relapse of MM., Methods: We first investigated the dynamics of serum sHLA-G, vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in 57 successfully treated MM patients undergoing remission and relapse. The interactions among these angiogenesis-related targets (sHLA-G, VEGF and IL-6) were examined in vitro. Their expression at different oxygen concentrations was investigated using a xenograft animal model by intra-bone marrow and skin grafts with myeloma cells., Results: We found that HLA-G protein degradation augmented angiogenesis. Soluble HLA-G directly inhibited vasculature formation in vitro. Mechanistically, HLA-G expression was regulated by hypoxia-inducible factor-1α (HIF-1α) in MM cells under hypoxia. We thus developed two mouse models of myeloma xenografts in intra-bone marrow (BM) and underneath the skin, and found a strong correlation between HLA-G and HIF-1α expressions in hypoxic BM, but not in oxygenated tissues. Yet when stimulated with IL-6, both HLA-G and HIF-1α could be targeted to ubiquitin-mediated degradation via PARKIN., Conclusion: These results highlight the importance of sHLA-G in angiogenesis at different phases of multiple myeloma. The experimental evidence that sHLA-G as an angiogenesis suppressor in MM may be useful for future development of novel therapies to prevent relapse., (© 2024. The Author(s).)
- Published
- 2024
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