PDF(Pubmed)
Abstract：
Breast cancer (BC) cells have a high risk of metastasis due to epithelial-mesenchymal transition (EMT). Palbociclib (CDK4/6 inhibitor) is an approved drug for BC treatment. However, the drug resistance and metastasis can impair the treatment outcome of Palbociclib. Understanding the mechanisms of EMT and Palbociclib drug resistance in BC is conducive to the formulation of novel therapeutic strategy. Here, we investigated the role of circHIAT1/miR-19a-3p/CADM2 axis in modulating EMT and Palbociclib resistance in BC. circHIAT1 and CADM2 were down-regulated in BC tissues and cell lines, and miR-19a-3p showed an up-regulation. circHIAT1 could interact with miR-19a-3p and suppress its activity, while miR-19a-3p functioned to negatively regulate CADM2. Forced over-expression of circHIAT1 could impaired the EMT status and migratory ability of BC cells, and this effect was inhibited by miR-19a-3p mimic. In addition, we also generated Palbociclib resistant BC cells, and showed that circHIAT1 and CADM2 were down-regulated in the resistant BC cells while miR-19a-3p showed an up-regulation. Forced circHIAT1 over-expression re-sensitized BC cells to Palbociclib treatment. Quercetin, a bioactive flavonoid, could suppressed the migration and invasion of BC cells, and re-sensitized BC cells to Palbociclib. The anti-cancer effect of quercetin could be attributed to its regulatory effect on circHIAT1/miR-19a-3p/CADM2 axis. In vivo tumorigenesis experiment further revealed that quercetin administration enhanced the anti-cancer effect of Palbociclib, an effect was dependent on the up-regulation of circHIAT1 by quercetin. In summary, this study identified quercetin as a potential anti-cancer compound to reverse Palbociclib resistance and impair EMT in BC cells by targeting circHIAT1/miR-19a-3p/CADM2 axis.
摘要：
由于上皮-间质转化（EMT），乳腺癌（BC）细胞具有很高的转移风险。Palbociclib（CDK4/6抑制剂）是一种批准用于BC治疗的药物。然而,耐药和转移可影响Palbociclib的治疗效果。了解BC中EMT和Palbociclib耐药的机制有助于制定新的治疗策略。这里,我们研究了circHIAT1/miR-19a-3p/CADM2轴在调节BCEMT和Palbociclib耐药中的作用.cirHIAT1和CADM2在BC组织和细胞系中下调，和miR-19a-3p显示上调。cirHIAT1可以与miR-19a-3p相互作用并抑制其活性，而miR-19a-3p负向调节CADM2。circHIAT1的过度表达可损害BC细胞的EMT状态和迁移能力,这种效应被miR-19a-3p模拟物抑制。此外,我们还产生了Palbociclib抗性BC细胞，并显示circHIAT1和CADM2在抗性BC细胞中下调，而miR-19a-3p显示上调。强制circHIAT1过表达使BC细胞对Palbociclib治疗敏感。槲皮素,一种生物活性类黄酮,可以抑制BC细胞的迁移和侵袭，并使BC细胞对Palbociclib重新敏感。槲皮素的抗癌作用可归因于其对circHIAT1/miR-19a-3p/CADM2轴的调节作用。体内肿瘤发生实验进一步表明槲皮素的给药增强了Palbociclib的抗癌作用，该效应依赖于槲皮素对circHIAT1的上调。总之,这项研究确定槲皮素是一种潜在的抗癌化合物,可通过靶向circHIAT1/miR-19a-3p/CADM2轴来逆转Palbociclib耐药并损害BC细胞EMT.
