MiR-101-3p inhibits MTX-mediated HMGB1 release and reduces recruitment and M1-like polarization of macrophages through the UBE2D1/KAT2B pathway.

The results of recent studies have shown that miRNAs play a vital role in tumor microenvironment during Methotrexate (MTX) chemotherapy. In this study, we investigated the possible miRNA changes and their effect of MTX on the U87 cell line. Our study found that MTX treatment up-regulated the secretion of HMGB1 and down-regulated the expression level of miR-101-3p. Data from ubiquitination and luciferase test showed that miR-101-3p can bind to UBE2D1 and reduce its ability to degrade KAT2B. Our data showed that KAT2B mediates the acetylation of HMGB1，and the acetylation of HMGB1 makes it dissociated from SIRT1 and thus be secreted outside the cell. Data from transwell and flow cytometry showed that RAW264.7 cells could take up HMGB1 secreted by U87 cells, promoting its M1-like polarization and recruitment. In summary, our results indicate that MTX may promote the differentiation and migration of macrophages through the UBE2D1/KAT2B/HMGB1 pathway, and miR-101-3p plays as an negative regulator on this pathway. This article is protected by copyright. All rights reserved.