CircPTK2/PABPC1/SETDB1 axis promotes EMT-mediated tumor metastasis and gemcitabine resistance in bladder cancer
CircPTK2/PABPC1/SETDB1 axis promotes EMT-mediated tumor metastasis and gemcitabine resistance in bladder cancer
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DOI：
10.1016/j.canlet.2022.216023
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发表时间：
2022-11-29
期刊：
影响因子：
9.7
通讯作者：
Dong, Wei
中科院分区：
文献类型：
--
作者：
Meng, Xiangui;Xiao, Wen;Dong, Wei
膀胱癌是泌尿系统最常见的恶性肿瘤之一，具有高度侵袭、转移、复发和化疗耐药的特点。最近的研究强调了circRNA-蛋白质复合物在肿瘤发生中的潜在影响。然而，circRNA-蛋白复合物调节BCa转移和化学抗性的机制仍然难以捉摸。在此，我们通过RNA测序分析转录组，鉴定了一种上调的circRNA，circPTK 2，其可以调节SETDB 1的表达。重要的是，使用circRNA下拉测定和RNA结合蛋白免疫沉淀，我们确定PABPC 1作为一个强大的新的相互作用蛋白circPTK 2。在机制上，circPTK 2可以结合PABPC 1并增强其稳定SETDB 1 mRNA的能力，从而特异性地促进SETDB 1表达并促进SETDB 1介导的上皮-间质转化（EMT）。在功能上，circPTK 2-SETDB 1轴的过表达在体外显著促进迁移、侵袭和吉西他滨耐药，并在体内增强淋巴结转移。总的来说，我们的研究结果阐明了迄今为止尚未探索的circPTK 2/PABPC 1/SETDB 1轴在BCa中EMT介导的肿瘤转移和吉西他滨耐药中的机制。
Bladder cancer (BCa), characterized by high invasion, metastasis, recurrence, and chemoresistance, is one of the most prevalent urologic malignant tumors. Recent studies have highlighted the potential impact of the circRNAs-protein complex in tumorigenesis. However, the mechanisms by which the circRNAs-protein complex regulates BCa metastasis and chemoresistance remain elusive. Herein, we identified an upregulated circRNA, circPTK2, which could regulate SETDB1 expression by analyzing the transcriptome by RNA-sequencing. Importantly, using circRNA pulldown assay and RNA-binding protein immunoprecipitation, we identified PABPC1 as a robust novel interacting protein of circPTK2. Mechanistically, circPTK2 could bind to PABPC1 and enhance its ability to stabilize SETDB1 mRNA, thereby specifically promoting SETDB1 expression and facilitating SETDB1-mediated epithelial-mesenchymal transition (EMT). Functionally, overexpression of the circPTK2-SETDB1 axis markedly promoted migration, invasion, and gemcitabine resistance in vitro and enhanced lymph node metastasis in vivo. Collectively, our findings clarified a hitherto unexplored mechanism of the circPTK2/PABPC1/SETDB1 axis in EMT-mediated tumor metastasis and gemcitabine resistance in BCa.