利基
膀胱癌
癌症
癌症研究
癌相关成纤维细胞
生物
肿瘤科
癌细胞
医学
内科学
生态学
作者
Junlong Zhuang,Lan Shen,Meiqian Li,Jingya Sun,Jiange Hao,Jiaxuan Li,Zhen Zhu,Shuning Ge,Dianzheng Zhang,Hongqian Guo,Ruimin Huang,Jun Yan
标识
DOI:10.1158/0008-5472.c.6628624
摘要
<div>Abstract<p>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 <i>SVEP1</i> in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3’UTR of mRNAs of <i>ARID1A</i> and <i>PRKAA2</i> (also known as <i>AMPKα2</i>) 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 <i>PRKAA2</i> 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.</p></div>
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