MiR-93 suppresses tumorigenesis and enhances chemosensitivity of breast cancer via dual targeting E2F1 and CCND1
MiR-93 suppresses tumorigenesis and enhances chemosensitivity of breast cancer via dual targeting E2F1 and CCND1
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MiR-93通过双靶向E2F1和CCND1抑制肿瘤发生并增强乳腺癌的化疗敏感性
DOI：
10.1038/s41419-020-02855-6
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发表时间：
2020-08-14
影响因子：
9
通讯作者：
Fan, Weimin
中科院分区：
文献类型：
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作者：
Bao, Chang;Chen, Jishun;Fan, Weimin
在临床实践中，肿瘤的化疗耐药常常导致治疗失败，这强调了发现新的治疗策略的关键需求。越来越多的证据表明，microRNAs （miRNAs）广泛参与肿瘤发生，但其在化疗耐药中的作用仍未得到充分的研究。在本研究中，我们发现miR-93-5p （miR-93）在体外和体内均能显著抑制细胞增殖，诱导G1/S细胞周期阻滞，并增加对紫杉醇（PTX）的化学敏感性。此外，两个已确定的癌基因E2F1和CCND1被确定为miR-93的双靶点。低表达E2F1和CCND1可降低细胞增殖和ptx敏感性，而过表达E2F1和CCND1则具有相反的作用。更重要的是，过表达E2F1和CCND1可拮抗mir -93介导的细胞周期阻滞和凋亡。进一步的机制研究表明，miR-93通过直接靶向E2F1和CCND1，灭活pRB/E2F1通路和AKT磷酸化，发挥其抑制作用。综上所述，我们的研究结果表明，miR-93极大地提高了化疗敏感性，并有可能成为乳腺癌治疗的新靶点。
Chemoresistance of tumors often leads to treatment failure in clinical practice, which underscores pivotal needs to uncover novel therapeutic strategies. Accumulating evidences show that microRNAs (miRNAs) are widely involved in carcinogenesis, but their function on chemoresistance remains largely unexplored. In this study, we found that miR-93-5p (miR-93) significantly inhibited cell proliferation, induced G1/S cell cycle arrest and increased chemosensitivity to paclitaxel (PTX) in vitro and in vivo. Moreover, two well-established oncogenes, E2F1 and CCND1, were identified as dual targets of miR-93. Knockdown of E2F1 and CCND1 reduced cell proliferation and PTX-sensitivity, whereas overexpression of them had the opposite effect. More importantly, overexpression of E2F1 and CCND1 antagonized miR-93-mediated cell cycle arrest and apoptosis. Further mechanistic study revealed that miR-93 exhibited its inhibitory role by directly targeting E2F1 and CCND1 to inactivate pRB/E2F1 pathway and AKT phosphorylation. Taken together, our findings suggested that miR-93 greatly improved chemosensitivity and potentially served as a novel therapeutic target for breast cancer treatment.