Circular RNA cESRP1 sensitises small cell lung cancer cells to chemotherapy by sponging miR-93-5p to inhibit TGF-β signalling
Circular RNA cESRP1 sensitises small cell lung cancer cells to chemotherapy by sponging miR-93-5p to inhibit TGF-β signalling
复制标题
环状RNA cESRP1通过海绵miR-93-5p抑制TGF-β信号传导使小细胞肺癌细胞对化疗敏感
DOI：
10.1038/s41418-019-0455-x
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发表时间：
2020-05-01
影响因子：
12.4
通讯作者：
Guo, Linlang
中科院分区：
文献类型：
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作者：
Huang, Weimei;Yang, Yunchu;Guo, Linlang
环状RNA（circRNAs）是一类新型的RNA分子，在包括乳腺癌和胃癌在内的不同癌症的化疗耐药性中发挥重要作用。然而，circRNAs是否参与小细胞肺癌（SCLC）对化疗的反应在很大程度上仍然未知。在本研究中，我们观察到与亲代化疗敏感细胞相比，cESRP1（环状RNA上皮剪接调节蛋白 - 1）在化疗耐药细胞中的表达显著下调。cESRP1通过抑制小细胞肺癌中的miR - 93 - 5p增强药物敏感性。细胞质中的cESRP1可直接与miR - 93 - 5p结合，并抑制由miR - 93 - 5p介导的转录后抑制，从而上调miR - 93 - 5p下游靶点Smad7 / p21（CDKN1A）的表达，并形成一个负反馈回路来调节转化生长因子 - β（TGF - β）介导的上皮 - 间质转化。此外，在一个获得性化疗耐药的患者来源的异种移植模型中，cESRP1过表达和TGF - β通路抑制均改变了肿瘤对化疗的反应性。重要的是，cESRP1在小细胞肺癌患者组织中的表达下调，并且与生存相关。我们的研究结果首次揭示，cESRP1通过吸附miR - 93 - 5p抑制TGF - β通路，在小细胞肺癌化疗敏感性中发挥关键作用，这表明cESRP1可能作为小细胞肺癌患者有价值的预后生物标志物和潜在的治疗靶点。
Circular RNAs (circRNAs) are novel RNA molecules that play important roles in chemoresistance in different cancers, including breast and gastric cancers. However, whether circRNAs are involved in the response to chemotherapy in small cell lung cancer (SCLC) remains largely unknown. In this study, we observed that cESRP1 (circular RNA epithelial splicing regulatory protein-1) expression was significantly downregulated in the chemoresistant cells compared with the parental chemosensitive cells. cESRP1 enhanced drug sensitivity by repressing miR-93-5p in SCLC. Cytoplasmic cESRP1 could directly bind to miR-93-5p and inhibit the posttranscriptional repression mediated by miR-93-5p, thereby upregulating the expression of the miR-93-5p downstream targets Smad7/p21(CDKN1A) and forming a negative feedback loop to regulate transforming growth factor-beta (TGF-beta) mediated epithelial-mesenchymal transition. Furthermore, cESRP1 overexpression and TGF-beta pathway inhibition both altered tumour responsiveness to chemotherapy in an acquired chemoresistant patient-derived xenograft model. Importantly, cESRP1 expression was downregulated in SCLC patient tissues and was associated with survival. Our findings reveal, for the first time, that cESRP1 plays crucial a role in SCLC chemosensitivity by sponging miR-93-5p to inhibit the TGF-beta pathway, suggesting that cESRP1 may serve as a valuable prognostic biomarker and a potential therapeutic target in SCLC patients.