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KMID : 0381120190410111273
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Genes and Genomics
2019 Volume.41 No. 11 p.1273 ~ p.1280
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Upregulation of S100A9 contributes to the acquired resistance to BRAF inhibitors
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Hwang Sung-Hee
Ahn Jun-Ho
Lee Michael
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Abstract
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Backgrounds: Acquired resistance is a significant clinical challenge in targeted therapy of melanomas using BRAF inhibitors. We previously identified that downregulation of miR-92a-1-5p confers acquired resistance to BRAF inhibition using an miRNA array platform.
Objective: In this study, we investigated the target genes of miR-92a-1-5p and their functional significance in BRAF inhibitor resistance.
Methods: The miRNA target prediction data were combined with RNA-Seq data to identify possible target genes for miR-92a-1-5p. Cellular effects of target genes were further examined using siRNA knockdown, WST-1 assay, and immunoblotting analysis.
Results: We selected S100 calcium-binding protein A9 (S100A9) as a possible target gene for functional validation. S100A9 knockdown abrogated resistance to PLX4720 in A375P/Mdr cells. This result was similar to those described earlier for miR-92a-1-5p, indicating that miR-92a-1-5p inhibits cell viability by targeting S100A9. S100A9 overexpression partially conferred PLX4720 resistance to A375P cells. We also demonstrated that MAPK re-activation does not contribute to the promotion of BRAF inhibitor resistance by S100A9.
Conclusion: Taken together, our results indicate that S100A9 might be functionally involved in development of resistance to BRAF inhibitors and might be a target for melanoma therapy in the future.
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KEYWORD
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BRAF inhibitor, Drug resistance, S100A9, miRNA, RNA-Seq analysis
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