The main etiopathogenesis of rheumatoid arthritis (RA) is overexpressed inflammatory cytokines and tissue injury mediated by persistent NF-κB activation. MicroRNAs widely participate in the regulation of target gene expression and play important roles in various diseases. Here, we explored the mechanisms of microRNAs in RA. We found that microRNA (miR)-10a was downregulated in the fibroblast-like synoviocytes (FLSs) of RA patients compared with osteoarthritis (OA) controls, and this downregulation could be triggered by TNF-α and IL-1β in an NF-κB-dependent manner through promoting the expression of the YingYang 1 (YY1) transcription factor. Downregulated miR-10a could accelerate IκB degradation and NF-κB activation by targeting IRAK4, TAK1 and BTRC. This miR-10a-mediated NF-κB activation then significantly promoted the production of various inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-8, and MCP-1, and matrix metalloproteinase (MMP)-1 and MMP-13. In addition, transfection of a miR-10a inhibitor accelerated the proliferation and migration of FLSs. Collectively, our data demonstrates the existence of a novel NF-κB/YY1/miR-10a/NF-κB regulatory circuit that promotes the excessive secretion of NF-κB-mediated inflammatory cytokines and the proliferation and migration of RA FLSs. Thus, miR-10a acts as a switch to control this regulatory circuit and may serve as a diagnostic and therapeutic target for RA treatment.

Tamoxifen remains the most effective treatment for estrogen receptor α (ERα)‐positive breast cancer. However, many patients still develop resistance to tamoxifen in association with metastatic recurrence, which presents a tremendous clinical challenge. To better understand tamoxifen resistance from the perspective of the tumor microenvironment, the whole microenvironment landscape is charted by single‐cell RNA sequencing and a new cancer‐associated fibroblast (CAF) subset, CD63 + CAFs, is identified that promotes tamoxifen resistance in breast cancer. Furthermore, it is discovered that CD63 + CAFs secrete exosomes rich in miR‐22, which can bind its targets, ER α and PTEN, to confer tamoxifen resistance on breast cancer cells. Additionally, it is found that the packaging of miR‐22 into CD63 + CAF‐derived exosomes is mediated by SFRS1. Furthermore, CD63 induces STAT3 activation to maintain the phenotype and function of CD63 + CAFs. Most importantly, the pharmacological blockade of CD63 + CAFs with a CD63‐neutralizing antibody or cRGD‐miR‐22‐sponge nanoparticles enhances the therapeutic effect of tamoxifen in breast cancer. In summary, the study reveals a novel subset of CD63 + CAFs that induces tamoxifen resistance in breast cancer via exosomal miR‐22, suggesting that CD63 + CAFs may be a novel therapeutic target to enhance tamoxifen sensitivity.

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Oestrogen receptor alpha (ERa) is a well-known target of endocrine therapy for ERa-positive breast cancer. ERa-negative cells, which are enriched during endocrine therapy, are associated with metastatic relapse. Here we determine that loss of ERa in the invasive front and in lymph node metastasis in human breast cancer is significantly correlated with lymphatic metastasis. Using in vivo and in vitro experiments, we demonstrate that ERa inhibits breast cancer metastasis. Furthermore, we find that ERa is a novel regulator of vinculin expression in breast cancer. Notably, ERa suppresses the amoeboid-like movement of breast cancer cells by upregulating vinculin in 3D matrix, which in turn promotes cell-cell and cell-matrix adhesion and inhibits the formation of amoeboid-like protrusions. A positive association between ERa and vinculin expression is found in human breast cancer tissues. The results show that ERa inhibits breast cancer metastasis and suggest that ERa suppresses cell amoeboid-like movement by upregulating vinculin.