癌干细胞（CSC）在许多癌症类型（包括尿路上皮膀胱癌（UBC））的化疗抗性和复发中发挥关键作用。除了内在信号通路外，肿瘤微环境（TME）中来自细胞外的信号对于CSC的维持是必不可少的。为了更好地了解TME介导UBC CSC产生和支持的机制，我们在本研究中专注于癌相关成纤维细胞（CAF）的作用。在CAF中过表达miR-146a-5p可以促进CAF与UBC细胞的相互作用、增强癌干性、并增强对吉西他滨和顺铂治疗的耐药性。机制上，miR-146-5p通过增强转录因子YY1的招募而上调了CAF中的SVEP1表达。同时，CAF分泌的miR-146a-5p通过靶向UBC细胞中ARID1A和PRKAA2（也称AMPKα2）mRNA的3'UTR来促进癌干性和耐药性。ARID1A的下调导致SOCS1的抑制和随后STAT3的激活，而PRKAA2的下调则导致mTOR信号的激活。UBC患者血清中升高的外泌体miR-146a-5p水平与肿瘤分期和复发风险都有关。这些研究发现表明CAF来源的miR-146a-5p可以促进UBC中的干性和增强耐药性。外泌体miR-146a-5p可能是UBC复发的生物标志物和潜在治疗靶点。

Cancer stem-like cells (CSCs) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAFs) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin. Mechanistically, miR-146-5p upregulated SVEP1 in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3'UTR of mRNAs of ARID1A and PRKAA2 (also known as AMPKα2) in UBC cells, CAF-secreted miR-146a-5p promoted cancer stemness and chemoresistance. Downregulation of ARID1A resulted in the inhibition of SOCS1 and subsequent STAT3 activation, and downregulated PRKAA2 led to the activation of mTOR signaling. Elevated levels of exosomal miR-146a-5p in the serum of UBC patients were correlated with both tumor stage and relapse risk. These findings altogether indicate that CAF-derived miR-146a-5p can promote stemness and enhance chemoresistance in UBC. Exosomal miR-146a-5p may be a biomarker of UBC recurrence and a potential therapeutic target.