Circular RNA circBFAR promotes the progression of pancreatic ductal adenocarcinoma via the miR-34b-5p/MET/Akt axis
Circular RNA circBFAR promotes the progression of pancreatic ductal adenocarcinoma via the miR-34b-5p/MET/Akt axis
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环状RNA circBFAR通过miR-34b-5p/MET/Akt轴促进胰腺导管腺癌的进展
DOI：
10.1186/s12943-020-01196-4
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发表时间：
2020-05-06
期刊：
影响因子：
37.3
通讯作者：
Chen, Changhao
中科院分区：
文献类型：
--
作者：
Guo, Xiaofeng;Zhou, Quanbo;Chen, Changhao
背景越来越多的证据表明，环状RNA（circRNA）是癌症进展的重要参与者。然而，circRNA在胰腺导管腺癌（PDAC）中的生物学过程和潜在机制尚不清楚。方法通过Sanger测序验证CircRNA。通过集落形成、5-乙炔基-2'-脱氧尿苷 (EdU) 和 Transwell 实验来研究 circBFAR 对体外 PDAC 细胞增殖、侵袭和迁移的影响。进行 RNA Pull-down 测定来验证 circBFAR 与 microRNA miR-34b-5p 的结合。结果在本研究中，我们鉴定了一种新型 circRNA（称为 circBFAR，hsa_circ_0009065），它在 208 例 PDAC 患者队列中表达上调。 circBFAR的异位表达与肿瘤淋巴结转移（TNM）分期呈正相关，并且与PDAC患者较差的预后相关。此外，circBFAR 敲低可显着抑制体外 PDAC 细胞的增殖和运动，以及体内模型中的肿瘤促进和转移特性。从机制上讲，circBFAR 通过海绵 miR-34b-5p 上调间充质上皮转化因子 (MET) 表达。此外，circBFAR过表达增加了MET的表达并激活了Akt（Ser 473）下游磷酸化，进一步激活了MET/PI3K/Akt信号通路，最终促进了PDAC细胞的进展。重要的是，MET抑制剂的应用可以显着减弱circBFAR介导的体内肿瘤发生。结论我们的研究结果表明，circBFAR在PDAC的增殖和转移中发挥重要作用，这可能会被探索作为PDAC的潜在预后标志物和治疗靶点。
BackgroundAccumulating evidence suggests that circular RNAs (circRNAs) are important participants in cancer progression. However, the biological processes and underlying mechanisms of circRNAs in pancreatic ductal adenocarcinoma (PDAC) are unclear.MethodCircRNAs were verified by Sanger sequencing. Colony formation, 5-Ethynyl-2′-deoxyuridine (EdU), and Transwell assays were performed to investigate the effect of circBFAR on the proliferation, invasion, and migration of PDAC cells in vitro. RNA pull-down assays were conducted to verify the binding of circBFAR with microRNA miR-34b-5p.ResultsIn the present study, we identified a novel circRNA (termed as circBFAR, hsa_circ_0009065) that was upregulated in a 208-case cohort of patients with PDAC. The ectopic expression of circBFAR correlated positively with the tumor-node-metastasis (TNM) stage and was related to poorer prognosis of patients with PDAC. Moreover, circBFAR knockdown dramatically inhibited the proliferation and motility of PDAC cells in vitro and their tumor-promoting and metastasis properties in in vivo models. Mechanistically, circBFAR upregulated mesenchymal-epithelial transition factor (MET) expression via sponging miR-34b-5p. Additionally, circBFAR overexpression increased the expression of MET and activated downstream phosphorylation of Akt (Ser 473) and further activated the MET/PI3K/Akt signaling pathway, which ultimately promoted the progression of PDAC cells. Importantly, application of MET inhibitors could significantly attenuate circBFAR-mediated tumorigenesis in vivo.ConclusionsOur findings showed that circBFAR plays an important role in the proliferation and metastasis of PDAC, which might be explored as a potential prognostic marker and therapeutic target for PDAC.