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Genes & Genomics

, Volume 41, Issue 11, pp 1273–1280 | Cite as

Upregulation of S100A9 contributes to the acquired resistance to BRAF inhibitors

  • Sung-Hee Hwang
  • Jun-Ho Ahn
  • Michael LeeEmail author
Research Article

Abstract

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.

Keywords

BRAF inhibitor Drug resistance S100A9 miRNA RNA-Seq analysis 

Notes

Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2016R1D1A1B03930193).

Compliance with ethical standards

Conflict of interest

Sung-Hee Hwang, Hun-Ho Ahn & Michael Lee declares that they have no conflict of interest.

Supplementary material

13258_2019_856_MOESM1_ESM.xls (90 kb)
Supplementary material 1 (XLS 90 kb)

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Copyright information

© The Genetics Society of Korea 2019

Authors and Affiliations

  1. 1.Division of Life Sciences, College of Life Sciences and BioengineeringIncheon National UniversityIncheonRepublic of Korea
  2. 2.System Toxicology Research CenterKorea Institute of ToxicologyDaejeonRepublic of Korea

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