Overexpression of miRNA-3613-3p Enhances the Sensitivity of Triple Negative Breast Cancer to CDK4/6 Inhibitor Palbociclib.
Overexpression of miRNA-3613-3p Enhances the Sensitivity of Triple Negative Breast Cancer to CDK4/6 Inhibitor Palbociclib.
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miRNA-3613-3p 的过表达增强了三阴性乳腺癌对 CDK4/6 抑制剂 Palbociclib 的敏感性
DOI：
10.3389/fonc.2020.590813
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发表时间：
2020
影响因子：
4.7
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Yu Y;Liao H;Xie R;Zhang Y;Zheng R;Chen J;Zhang B
三阴性乳腺癌 (TNBC) 的特点是缺乏雌激素和孕激素受体以及 HER2 的表达，而这些都是常见的治疗靶点。 CDK4/6抑制剂Palbociclib已被批准作为乳腺癌的抗癌药物。然而，识别预测 Palbociclib 反应的生物标志物一直是分子靶向治疗的一个挑战。在本研究中，我们将 microRNA 确定为 TNBC 患者的标志，并探讨 miR-3613-3p 是否可以作为三阴性乳腺癌患者的肿瘤抑制生物标志物，以及 miR-3613-3p 的过度表达是否可以增强 TNBC 细胞对 Palbociclib 的敏感性。我们发现，miR3613-3p 的表达在 TNBC 肿瘤和细胞中下调，并且患者肿瘤组织中 miR-3613-3p 的过表达在临床和病理学上与良好的预后相关，例如较小的肿瘤尺寸和较低的 Ki-67。在体外，miR-3613-3p 的过度表达抑制细胞增殖，诱导 G1 细胞周期停滞，并增强 TNBC 细胞对 Palbociclib 治疗的敏感性。体内研究表明，miR-3613-3p 的过表达可抑制 TNBC 肿瘤发生，Palbociclib 对 MDA-MB-231 细胞具有显着的抑制作用。从机制上讲，SMAD2 和 EZH2 被发现是 miR-3613-3p 的两个直接靶标，并通过诱导细胞衰老介导 TNBC 细胞的增殖以及细胞对 Palbociclib 的敏感性。我们的研究结果表明 miR-3613-3p 在 TNBC 中充当癌症抑制 miRNA。此外，我们的研究表明 miR-3613-3p 可用作 TNBC 对 Palbociclib 反应的预测生物标志物。
Triple negative breast cancer (TNBC) is characterized by lack of expression of the estrogen and progesterone receptors and HER2, which are common therapeutic targets. CDK4/6 inhibitor Palbociclib has been approved as an anti-cancer agent for breast cancer. However, identifying biomarkers that predict the response to Palbociclib has always been a challenge for molecular targeted therapy. In this study, we identify microRNA as a hallmark in TNBC patients and explore if miR-3613-3p might serve as a tumor suppressor biomarker for triple negative breast cancer patients and if overexpression of miR-3613-3p could enhance the sensitivity of TNBC cells to Palbociclib. We show that the expression of miR3613-3p was down-regulated in TNBC tumors and cells, and the overexpression of miR-3613-3p in patients’ tumor tissues was clinically and pathologically correlated with favorable prognosis, such as smaller tumor size and the lower Ki-67. In vitro, overexpression of miR-3613-3p inhibited cell proliferation, induced G1 cell-cycle arrest, and enhanced the sensitivity of TNBC cells to Palbociclib treatment. In vivo study revealed that overexpression of miR-3613-3p inhibited TNBC tumorigenesis and exerted a significant inhibitory effect of Palbociclib on MDA-MB-231 cells. Mechanically, SMAD2 and EZH2 were found to be two direct targets of miR-3613-3p and mediate the proliferation of TNBC cells and the sensitivity of the cells to Palbociclib through inducing cellular senescence. Our findings suggested that miR-3613-3p acts as a cancer-suppressor miRNA in TNBC. Moreover, our study showed that miR-3613-3p might be used as a predictive biomarker for the response of TNBC to Palbociclib.
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