MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1
MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1
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MiR-200b 和 miR-15b 通过靶向 BMI1 调节化疗诱导的人舌癌细胞上皮间质转化
DOI：
10.1038/onc.2011.263
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发表时间：
2012-01-01
期刊：
影响因子：
8
通讯作者：
Li, J.
中科院分区：
文献类型：
--
作者：
Sun, L.;Yao, Y.;Li, J.
据报道，化疗可诱导肿瘤细胞发生上皮 - 间质转化（EMT），这是转移过程中的关键步骤，会导致癌症扩散和治疗失败。然而，化疗诱导EMT的潜在机制仍不清楚，而且微小RNA（miRNA）在这一过程中的作用也知之甚少。为了解决这些问题，我们通过将亲本CAL27和SCC25细胞系暴露于浓度递增的顺铂中6个月，建立了稳定的舌鳞状细胞癌（TSCC）化疗耐药细胞系CAL27 - res和SCC25 - res。CAL27 - res和SCC25 - res细胞呈现间质特征，侵袭性和运动性增强。miRNA微阵列显示，miR - 200b和miR - 15b是CAL27 - res细胞中下调最显著的miRNAs。用miRNA模拟物异位表达miR - 200b和miR - 15b可有效逆转CAL27 - res和SCC25 - res细胞的EMT表型，并使其对化疗敏感，而用反义寡核苷酸抑制敏感细胞系中的miR - 200b和miR - 15b则诱导EMT并产生化疗耐药性。在miRNA模拟物存在的情况下，通过用在其3' - 非翻译区携带miR - 200b或miR - 15b突变种子序列的pcDNA3.1 - BMI1转染CAL27 - res细胞，恢复miR - 200b和miR - 15b的靶标B淋巴瘤Mo - MLV插入区1同源物（BMI1）的表达，重现了化疗诱导的EMT。在体内，强制表达miR - 200b或miR - 15b可抑制由CAL27 - res细胞建立的TSCC异种移植物的转移。在临床上，miR - 200b或miR - 15b表达降低与TSCC的化疗耐药性以及患者生存率低有关。我们的数据表明，miR - 200b和miR - 15b表达降低是TSCC中化疗诱导EMT的机制基础，并可作为逆转舌癌化疗耐药性的治疗靶点。《癌基因》（2012年）31卷，432 - 445页；doi:10.1038/onc.2011.263；2011年7月4日在线发表
Chemotherapy has been reported to induce epithelial-mesenchymal transition (EMT) in tumor cells, which is a critical step in the process of metastasis leading to cancer spreading and treatment failure. However, the underlying mechanisms of chemotherapy-induced EMT remain unclear, and the involvement of microRNAs (miRNA) in this process is poorly understood. To address these questions, we established stable chemotherapy-resistant tongue squamous cell carcinoma (TSCC) cell lines CAL27-res and SCC25-res by exposing the parental CAL27 and SCC25 lines to escalating concentrations of cisplatin for 6 months. CAL27-res and SCC25-res cells displayed mesenchymal features with enhanced invasiveness and motility. MiRNA microarray illustrated that miR-200b and miR-15b were the most significantly downregulated microRNAs in CAL27-res cells. Ectopic expression of miR-200b and miR-15b with miRNA mimics effectively reversed the phenotype of EMT in CAL27-res and SCC25-res cells, and sensitized them to chemotherapy, but inhibition of miR-200b and miR-15b in the sensitive lines with anti-sense oligonucleotides induced EMT and conferred chemoresistance. Retrieving the expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a target for miR-200b and miR-15b, in the presence of the miRNA mimics by transfecting CAL27-res cells with pcDNA3. 1–BMI1-carrying mutated seed sequences of miR-200b or miR-15b at its 3′-UTR recapitulated chemotherapy-induced EMT. In vivo, enforced miR-200b or miR-15b expression suppressed metastasis of TSCC xenografts established by CAL27-res cells. Clinically, reduced miR-200b or miR-15b expression was associated with chemotherapeutic resistance in TSCCs and poor patient survival. Our data suggest that reduced expression of miR-200b and miR-15b underscores the mechanisms of chemotherapy-induced EMT in TSCC, and may serve as therapeutic targets to reverse chemotherapy resistance in tongue cancers.