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GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells

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Last modified
  • 06/25/2025
Type of Material
Authors
    Andrea Kosta, Sapienza University of RomeAbdelilah Mekhloufi, Emory UniversityLorenzo Lucantonio, Sapienza University of RomeAlessandra Zingoni, Sapienza University of RomeAlessandra Soriani, Sapienza University of RomeMarco Cippitelli, Sapienza University of RomeAngela Gismondi, Sapienza University of RomeFrancesca Fazio, Sapienza University of RomeMaria Teresa Petrucci, Sapienza University of RomeAngela Santoni, Sapienza University of RomeHelena Stabile, Sapienza University of RomeCinzia Fionda, Sapienza University of Rome
Language
  • English
Date
  • 2022-07-28
Publisher
  • Frontiers Media
Publication Version
Copyright Statement
  • © 2022 Kosta, Mekhloufi, Lucantonio, Zingoni, Soriani, Cippitelli, Gismondi, Fazio, Petrucci, Santoni, Stabile and Fionda
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Final Published Version (URL)
Title of Journal or Parent Work
Volume
  • 13
Grant/Funding Information
  • This work was supported by grants from andMinistero dell’Istruzione, dell’Università e della Ricerca (PRIN cod. 20174T7NXL and 2017NTK4HY), Ricerca Universitaria (RP120172A7CD4ACB).
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Abstract
  • NKG2D ligands play a relevant role in Natural Killer (NK) cell -mediated immune surveillance of multiple myeloma (MM). Different levels of regulation control the expression of these molecules at cell surface. A number of oncogenic proteins and miRNAs act as negative regulators of NKG2D ligand transcription and translation, but the molecular mechanisms sustaining their basal expression in MM cells remain poorly understood. Here, we evaluated the role of the growth arrest specific 6 (GAS6)/TAM signaling pathway in the regulation of NKG2D ligand expression and MM recognition by NK cells. Our data showed that GAS6 as well as MERTK and AXL depletion in MM cells results in MICA downregulation and inhibition of NKG2D-mediated NK cell degranulation. Noteworthy, GAS6 derived from bone marrow stromal cells (BMSCs) also increases MICA expression at both protein and mRNA level in human MM cell lines and in primary malignant plasma cells. NF-kB activation is required for these regulatory mechanisms since deletion of a site responsive for this transcription factor compromises the induction of mica promoter by BMSCs. Accordingly, knockdown of GAS6 reduces the capability of BMSCs to activate NF-kB pathway as well as to enhance MICA expression in MM cells. Taken together, these results shed light on molecular mechanism underlying NKG2D ligand regulation and identify GAS6 protein as a novel autocrine and paracrine regulator of basal expression of MICA in human MM cells.
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Keywords
Research Categories
  • Health Sciences, Oncology
  • Engineering, Biomedical

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