miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma.
miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma.
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DOI：
10.1158/0008-5472.can-17-1318
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发表时间：
2018-02-15
期刊：
影响因子：
11.2
通讯作者：
Teixidó J
中科院分区：
文献类型：
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作者：
Díaz-Martínez M;Benito-Jardón L;Alonso L;Koetz-Ploch L;Hernando E;Teixidó J
用BRAF V600 E抑制剂维罗非尼（VMF）治疗黑色素瘤提供了治疗益处，但常见的耐药性仍然是一个挑战。我们产生了对VMF具有抗性的A375黑色素瘤细胞，目的是研究可能导致抗性的miRNA表达模式的变化。在VMF抗性细胞中发生的miR-204- 5 p和miR-211- 5 p的表达增加被确定为影响VMF响应。VMF处理通过RNA稳定化迅速影响它们的表达。MEK和ERK抑制剂引起了类似的作用，但AKT或Rac抑制剂没有。两种miRNA在未用药的人黑色素瘤细胞中的异位表达足以赋予VMF抗性和体内更稳健的肿瘤生长。相反，在抗性细胞中沉默它们的表达会抑制细胞生长。在VMF暴露后，miR-204- 5 p和miR-211- 5 p的联合过表达持续刺激Ras和MAPK上调。总体而言，我们的研究结果显示了VMF治疗后miR-204- 5 p和miR-211- 5 p的上调如何导致耐药性的出现，这对基于机制的策略改善VMF反应具有潜在意义。
Melanoma treatment with the BRAF V600E inhibitor vemurafenib (VMF) provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to VMF with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in VMF-resistant cells was determined to impact VMF response. Their expression was rapidly affected by VMF treatment through RNA stabilization. Similar effects were elicited by MEK and ERK inhibitors but not AKT or Rac inhibitors. Ectopic expression of both miRNA in drug-naive human melanoma cells was sufficient to confer VMF resistance and more robust tumor growth in vivo. Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after VMF exposure. Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following VMF treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve VMF responses.