circKDM4C suppresses tumor progression and attenuates doxorubicin resistance by regulating miR-548p/PBLD axis in breast cancer
circKDM4C suppresses tumor progression and attenuates doxorubicin resistance by regulating miR-548p/PBLD axis in breast cancer
复制标题
circKDM4C 通过调节乳腺癌中的 miR-548p/PBLD 轴抑制肿瘤进展并减弱阿霉素耐药性
DOI：
10.1038/s41388-019-0926-z
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发表时间：
2019-10-17
期刊：
影响因子：
8
通讯作者：
Yang, Qifeng
中科院分区：
文献类型：
--
作者：
Liang, Yiran;Song, Xiaojin;Yang, Qifeng
越来越多的证据表明，环状RNA（circRNA）在癌症发展中起着关键作用。然而，只有少量的circRNA已被实验验证和功能注释。在这项研究中，使用高通量微阵列分析，我们确定了一种新的circRNA，circKDM 4C，这是在乳腺癌转移组织下调。此外，我们分析了一组乳腺癌患者，发现乳腺癌组织中circKDM 4C表达降低，circKDM 4C表达降低与乳腺癌的预后不良和转移相关。在功能上，我们证明了circKDM 4C在体外和体内显著抑制乳腺癌增殖、转移和多柔比星抗性。在机制上，使用双荧光素酶活性测定和AGO 2 RNA免疫沉淀，将circKDM 4C鉴定为miR-548 p海绵。我们还发现PBLD是miR-548 p的直接靶点，miR-548 p在乳腺癌中起肿瘤抑制作用。此外，miR-548 p过表达能够逆转circKDM 4C诱导的乳腺癌细胞恶性表型的减弱和PBLD表达的升高。综上所述，我们的数据表明circKDM 4C可能具有相当大的潜力作为乳腺癌的预后生物标志物，并支持circKDM 4C/miR-548 p/PBLD轴的治疗靶向可能是乳腺癌患者有希望的治疗方法的观点。
Increasing evidence has indicated that circular RNAs (circRNAs) play a critical role in cancer development. However, only a small number of circRNAs have been experimentally validated and functionally annotated. In this study, using a high-throughput microarray assay, we identified a novel circRNA, circKDM4C, which was downregulated in breast cancer tissues with metastasis. Furthermore, we analyzed a cohort of breast cancer patients and found that circKDM4C expression was decreased in breast cancer tissues, and lower circKDM4C expression was associated with poor prognosis and metastasis in breast cancer. Functionally, we demonstrated that circKDM4C significantly repressed breast cancer proliferation, metastasis, and doxorubicin resistance in vitro and in vivo. Mechanistically, using a dual-luciferase activity assay and AGO2 RNA immunoprecipitation, circKDM4C was identified as a miR-548p sponge. We also found that PBLD was a direct target of miR-548p, which functioned as a tumor suppressor in breast cancer. Moreover, miR-548p overexpression was able to reverse the circKDM4C-induced attenuation of malignant phenotypes and elevated expression of PBLD in breast cancer cells. Taken together, our data indicate that circKDM4C might have considerable potential as a prognostic biomarker in breast cancer, and support the notion that therapeutic targeting of circKDM4C/miR-548p/PBLD axis may be a promising treatment approach for breast cancer patients.