Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of Neck Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Basic Clin Pharmacol Toxicol. 2018 Dec;123(6):670-677. doi: 10.1111/bcpt.13076. Epub 2018 Aug 5.
Chemotherapy is one of the most effective forms of cancer treatment. It has been widely used in the treatment of various malignant tumours. To investigate molecular mechanisms responsible for the chemoresistance of anaplastic thyroid cancer (ATC), we established the doxorubicin (Dox) resistance of human ATC SW1736 and 8305C cells and named them SW1736/Dox and 8305C/Dox, respectively. We evaluated the expression of various micro-RNAs (miRNAs) between control and Dox-resistant ATC cells and found that the expression of miR-27b-3p was significantly increased in Dox-resistant ATC cells. Targeted inhibition of miR-27b can increase the sensitivity of SW1736/Dox and 8305C/Dox cells. Bioinformatics analysis revealed that miR-27b can directly target peroxisome proliferator-activated receptor gamma (PPARγ) within the 3' untranslated region (UTR). This was proved by the results that miR-27b-3p down-regulated the protein and mRNA levels of PPARγ. While the mutant in the core binding sites of PPARγ abolished miR-27b-3p-induced down-regulation of luciferase activity. Over-expression of PPARγ can increase the Dox sensitivity of SW1736/Dox and 8305C/Dox cells. Basic fibroblast growth factor (bFGF) might be involved in miR-27b-3p/PPARγ-regulated Dox resistance of ATC cells. The activation of p65 nuclear factor-κB (NF-κB) regulated the up-regulation of miR-27b-3p in Dox-resistant ATC cells. Collectively, our data revealed that miR-27b-3p/PPARγ is involved in the Dox resistance of human ATC cells. It suggested that targeted inhibition of miR-27b-3p might be helpful to overcome the drug resistance of ATC cells.
化疗是癌症治疗中最有效的方法之一。它已被广泛用于治疗各种恶性肿瘤。为了研究导致间变性甲状腺癌（ATC）化疗耐药的分子机制，我们建立了多柔比星（Dox）耐药的人 ATC SW1736 和 8305C 细胞，并分别将其命名为 SW1736/Dox 和 8305C/Dox。我们评估了对照和 Dox 耐药 ATC 细胞之间各种 microRNA（miRNA）的表达，发现 miR-27b-3p 在 Dox 耐药 ATC 细胞中的表达显著增加。靶向抑制 miR-27b 可以增加 SW1736/Dox 和 8305C/Dox 细胞的敏感性。生物信息学分析显示，miR-27b 可以在 3'非翻译区（UTR）内直接靶向过氧化物酶体增殖物激活受体γ（PPARγ）。这一点通过 miR-27b-3p 下调 PPARγ 的蛋白和 mRNA 水平的结果得到证实。而在 PPARγ 的核心结合位点发生突变时，miR-27b-3p 诱导的荧光素酶活性下调被消除。过表达 PPARγ 可以增加 SW1736/Dox 和 8305C/Dox 细胞对 Dox 的敏感性。碱性成纤维细胞生长因子（bFGF）可能参与了 miR-27b-3p/PPARγ 调节的 ATC 细胞对 Dox 的耐药性。核因子-κB（NF-κB）p65 的激活调节了 Dox 耐药 ATC 细胞中 miR-27b-3p 的上调。总之，我们的数据表明 miR-27b-3p/PPARγ 参与了人 ATC 细胞的 Dox 耐药性。这表明靶向抑制 miR-27b-3p 可能有助于克服 ATC 细胞的耐药性。
