Treatment of advanced BRAFV600-mutant melanoma using BRAF inhibitors (BRAFi) eventually leads to drug resistance and selects for highly metastatic tumor cells. We compared the most differentially dysregulated miRNA expression profiles of vemurafenib-resistant and highly-metastatic melanoma cell lines obtained from GEO DataSets. We discovered miR-152-5p was a potential regulator mediating melanoma drug resistance and metastasis. Functionally, knockdown of miR-152-5p significantly compromised the metastatic ability of BRAFi-resistant melanoma cells and overexpression of miR-152-5p promoted the formation of slow-cycling phenotype. Furthermore, we explored the cause of how and why miR-152-5p affected metastasis in depth. Mechanistically, miR-152-5p targeted TXNIP which affected metastasis and BRAFi altered the methylation status of MIR152 promoter. Our study highlights the crucial role of miR-152-5p on melanoma metastasis after BRAFi treatment and holds significant implying that discontinuous dosing strategy may improve the benefit of advanced BRAFV600-mutant melanoma patients.

中文翻译：

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BRAFi诱导的miR-152-5p去甲基化通过靶向皮肤黑素瘤中的TXNIP来调节表型转换。

使用BRAF抑制剂（BRAFi）治疗晚期BRAFV600突变型黑色素瘤最终会导致耐药性，并选择高度转移性的肿瘤细胞。我们比较了从GEO数据集获得的对维罗非尼耐药和高度转移的黑色素瘤细胞系的差异最大的miRNA表达失调。我们发现miR-152-5p是介导黑色素瘤耐药性和转移的潜在调节剂。在功能上，敲低miR-152-5p显着损害了BRAFi抗性黑素瘤细胞的转移能力，miR-152-5p的过表达促进了慢循环表型的形成。此外，我们深入探讨了miR-152-5p如何以及为何影响转移的原因。从机制上讲，miR-152-5p靶向TXNIP会影响转移，BRAFi会改变MIR152启动子的甲基化状态。