EXOSC4通过IL-6促进ER+乳腺癌免疫逃逸的研究OA

Objective To investigate the mechanism by which EXOSC4,a core subunit of the RNA exosome,promotes immune escape in estrogen receptor-positive(ER+)breast cancer.Methods Negative-control and EXOSC4-targeting siRNAs and pcDNA3.1 and pcDNA3.1-EXOSC4 plasmids were transfected into MCF7 cells.RNA sequenc⁃ing(RNA-seq)was performed to identify candidate target genes shared by the EXOSC4-knockdown and EXOSC4-over⁃expression groups.Quantitative real-time reverse transcription polymerase chain reaction(qRT-PCR)was used to vali⁃date interleukin-6(IL-6)as a consistently altered target gene in MCF7 and T47D cells.Associations between EXOSC4 expression and immune effector molecules in ER+breast cancer were analyzed using the TIMER database.Western blotting was used to evaluate changes in IL-6/STAT3 pathway protein expression after EXOSC4 knockdown or overexpression.Cell co-culture assays were used to assess macrophage polarization after EXOSC4 knockdown com⁃bined with IL-6 overexpression or EXOSC4 overexpression combined with IL-6 knockdown.All experiments were inde⁃pendently repeated three times.Data were expressed as the mean±SD and analyzed using the t test or one-way analy⁃sis of variance with Tukey's post hoc test;P<0.05 was considered statistically significant.Results EXOSC4 acti⁃vated IL-6/STAT3 signaling in ER+breast cancer cells,was negatively associated with multiple immune effector mol⁃ecules,and promoted IL-6-dependent polarization of THP-1 cells toward an M2 macrophage phenotype.Conclusion IL-6 may be a direct target of EXOSC4 in ER+breast cancer.EXOSC4 may promote immune escape by activating IL-6/STAT3 signaling and inducing M2 macrophage polarization.