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2016年1月28日，《自然》（Nature）旗下《癌基因》（Oncogene）杂志正式发表了复旦大学肿瘤医院、复旦大学上海医学院、美国田纳西大学健康科学中心、温州医科大学附属第一医院的一项新研究，显示微RNA-621（miRNA-621，miR-621）可以通过抑制FBXO11和增强p53活性提高乳腺癌对化疗的敏感性。 MicroRNA（miRNA）是长约22nt的非编码RNA，在胚胎发育、细胞分化和器官生成等重要的生物学过程中承担关键性的调控功能。这些短RNA在天然细胞中大量存在，它们能与靶基因的mRNA配对并阻碍其翻译，在转录后水平上调控目标基因的表达。 近年来越来越多的证据表明，miRNA在癌症中起到了很重要的作用，与癌细胞增殖、生长和化疗敏感性密切相关。用miRNA来预测癌症患者对治疗的应答，是非常有前景的。 紫杉醇＋卡铂（PTX/CBP）是一种用于乳腺癌的新辅助化疗。研究人员发现，miR-621表达与PTX/CBP化疗敏感性有很强的关联。miR-621水平高，意味着乳腺癌患者能更好的应答PTX/CBP，更容易达到病理学完全缓解。在体外培养的乳腺癌细胞和移植瘤模型中，miR-621过表达可以促进细胞凋亡，提高癌细胞对PTX和CBP的敏感性。 研究显示，FBXO11是miR-621的直接作用目标。在乳腺癌中，miR-621水平与FBXO11表达呈负相关。FBXO11异位表达会减弱miR-621的促凋亡效果。与此一致的是，FBXO11高表达与乳腺癌患者预后差有关。 进一步研究表明，乳腺癌细胞的FBXO11与p53互作并抑制其活性。miR-621对FBXO11的抑制可以增强p53活性，促使乳腺癌细胞在化疗时凋亡。研究指出，miR-621可以作为预测性的生物学指标，也是潜在的乳腺癌治疗靶标。 Oncogene. 2016 Jan 28;35(4):448-58. MiRNA-621 sensitizes breast cancer to chemotherapy by suppressing FBXO11 and enhancing p53 activity. Xue J, Chi Y, Chen Y, Huang S, Ye X, Niu J, Wang W, Pfeffer LM, Shao ZM, Wu ZH, Wu J. Fudan University Shanghai Cancer Center, Shanghai, China. Shanghai Medical College, Fudan University, Shanghai, China. University of Tennessee Health Science Center, Memphis, TN, USA. First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China. MicroRNAs (miRNAs) have been demonstrated to have critical roles in regulating cancer cell proliferation, survival and sensitivity to chemotherapy. The potential application of using miRNAs to predict therapeutic response to cancer treatment holds high promise, but miRNAs with predictive value remain to be identified and underlying mechanisms have not been completely understood. Here, we show a strong correlation between miR-621 expression and chemosensitivity to paclitaxel plus carboplatin (PTX/CBP) regimen, an effective neoadjuvant chemotherapy for breast cancer patients. High level of miR-621 predicts better response to PTX/CBP regimen neoadjuvant chemotherapy in breast cancer patients, who also tend to achieve pathological complete response. Ectopic overexpression of miR-621 promoted apoptosis and increased chemosensitivity to PTX and CBP both in cultured breast cancer cells and in xenograft tumor model. We further show that FBXO11 is a direct functional target of miR-621 and miR-621 level is negatively correlated with FBXO11 expression in breast cancer patients. Ectopic expression of FBXO11 attenuated increased apoptosis in breast cancer cells overexpressing miR-621 upon PTX or CBP treatment. Consistently, high FBXO11 expression significantly correlated with poor survival in breast cancer patients. Mechanistically, we found in breast cancer cells FBXO11 interacts with p53 and promotes its neddylation, which suppressed the p53 transactivity. Accordingly, miR-621-dependent FBXO11 suppression enhanced p53 activity and increased apoptosis in breast cancer cells exposed to chemotherapeutics. Taken together, our data suggest that miR-621 enhances chemosensitivity of breast cancer cells to PTX/CBP chemotherapy by suppressing FBXO11-depedent inhibition of p53. miR-621 may serve as a predictive biomarker and a potential therapeutic target in breast cancer treatment. PMID: 25867061 DOI: 10.1038/onc.2015.96
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