Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells

Abstract

Abstract. Valproic acid, a histone deacetylase inhibitor, increases the expression of cell surface MHC class I-related chain molecules (MICs) A and B (MICA and B) in osteosarcoma cells and decreases their secretion of soluble MICA and MICB, which are produced by the proteolytic cleavage of cell surface MICs. Osteosarcoma cells have been reported to produce high levels of matrix metalloproteinase (MMP)-2 and -9. In this study, we investigated the involvement of MMP-2 and -9 in the inhibitory action of valproic acid (VPA) on the proteolytic cleavage of cell surface MICs using the U-2 OS and SaOS-2 osteosarcoma cell lines. VPA caused a marked decrease in the expression of MMP-9 mRNA in the U-2 OS and SaOS-2 cells and in the expression of MMP-2 mRNA in the U-2 OS cells, but only a slight decrease in the expression of MMP-2 mRNA in the SaOS-2 cells. The transfection of small interfering RNA (siRNA) for MMP-9 decreased the secretion of soluble MICA and MICB by both U-2 OS and SaOS-2 cells, but that of siRNA for MMP-2 did not. The present study therefore demonstrates that the downregulation of MMP-9 mRNA by VPA plays a role in the inhibitory action of VPA on the secretion of soluble MICA and MICB in osteosarcoma cells.

Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells

“…Soluble TL1AL72-L251 acts mainly in a paracrine manner to influence cells in the immune system, whereas the TL1AV84-L251 fragment acts via the autocrine pathway to induce the inhibition of the proliferation and apoptosis of endothelial cells (31). Our previous report indicated that VPA-treated OS cells do not exhibit increased ADAM17 gene transcription (32). Hence, the increase in the expression of soluble VEGI induced by HDAC inhibitors may involve a different mechanism of action than that mediating the shedding of membrane-bound VEGI.…”

Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention

“…Valproate treatment in osteosarcoma cells downregulates MMP9 expression and thereby enhances the expression of MICA and MICB ligands on the cell surface while downregulating the release of soluble forms of these ligands 79 . Moreover, the hypomethylating reagent hydralazine reduces the release of soluble form of MICA and MICB in conjunction with enhanced surface expression of these ligands 80 .…”

Clinical Significance of Soluble Major Histocompatibility Complex Class I Chain-related A in Renal Cell Carcinoma Patients

“…Our data collectively indicate that the release of sMICA is associated with tumor progression and metastasis in RCC. Shedding of NKG2D ligands, in particular MICA, from the cell surface represents a mechanism by which tumors escape NKG2D-mediated immunosurveillance (Kohga et al, 2012;Yamanegi et al, 2012). The production of sMICA has been found to impair NKG2D expression and NK cytotoxicity (Raffaghello et al, 2004).…”