MiR-451a attenuates doxorubicin resistance in lung cancer via suppressing epithelialmesenchymal transition (EMT) through targeting c-Myc
MiR-451a attenuates doxorubicin resistance in lung cancer via suppressing epithelialmesenchymal transition (EMT) through targeting c-Myc
复制标题
MiR-451a 通过靶向 c-Myc 抑制上皮间质转化 (EMT)，从而减弱肺癌中的阿霉素耐药性
DOI：
10.1016/j.biopha.2020.109962
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发表时间：
2020-05-01
影响因子：
7.5
通讯作者：
Lin-Fu, Zhou
中科院分区：
文献类型：
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作者：
Tao, Li;Shu-Ling, Wang;Lin-Fu, Zhou
化疗耐药仍然是肺癌治疗的主要障碍。越来越多的研究表明，microRNAs（miRNAs）是肿瘤进展过程中化疗耐药性的重要调节因子。据报道，miR-451 a是癌症发展过程中的肿瘤抑制因子。然而，其对肺癌的影响以及肺癌的耐药性仍不清楚。本研究结果显示，miR-451 a通过减轻上皮间质转化（EMT），在阿霉素（DOX）处理的肺癌细胞中表现出显著的耐药抑制作用，表现为N-cadherin和Vimentin的表达显著降低，而E-cadherin的表达增强。此外，miR-451 a过表达显著提高了肺癌细胞对DOX的敏感性，并破坏了肺癌细胞的EMT。在机制上，发现miR-451 a直接靶向c-Myc以影响肺癌细胞中响应于DOX孵育的EMT和耐药性。此外，c-Myc敲低显著提高了肺癌细胞对DOX的敏感性，而过表达c-Myc显著逆转了DOX的抗肿瘤作用，miR-451 a模拟物略微减弱了DOX的抗肿瘤作用。体内实验证实，miR-451 a通过减少c-Myc而促进肺癌细胞来源的肿瘤对DOX治疗的敏感性。因此，我们的研究结果揭示了肺癌细胞对DOX耐药的新见解，miR-451 a可被视为克服肺癌耐药的潜在治疗靶点。
Chemoresistance is still a major obstacle for lung cancer treatment. Increasing studies have demonstrated that microRNAs (miRNAs) are essential meditators of chemoresistance during cancer progression. MiR-451a is reported to be a tumor suppressor during cancer development. However, its effects on lung cancer and drug resistance in lung cancer are still unclear. In the study, the results showed that miR-451a exhibited a significant role in suppressing the drug resistance in lung cancer cells when treated with doxorubicin (DOX) through alleviating epithelialmesenchymal transition (EMT), as evidenced by the markedly reduced expression of N-cadherin and Vimentin, while the enhanced expression of E-cadherin. In addition, miR-451a over-expression markedly promoted the sensitivity of lung cancer cells to DOX treatments, and also disrupted the EMT of lung cancer cells. Mechanistically, miR-451a was found to directly target c-Myc to affect the EMT and drug resistance in lung cancer cells in response to DOX incubation. Furthermore, c-Myc knockdown markedly elevated the sensitivity of lung cancer cells to DOX, whereas over-expressing c-Myc markedly reversed the anti-tumor role of DOX, which was slightly diminished by miR-451a mimic. The in vivo experiments confirmed that miR-451a promoted the sensitivity of lung cancer cells-derived tumors to DOX treatment by reducing c-Myc. Therefore, our results revealed a new insight into DOX resistance of lung cancer cells and miR-451a could be considered as a potential therapeutic target to overcome drug resistance in lung cancer.