miR-7 reverses the resistance to BRAFi in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways.
miR-7 reverses the resistance to BRAFi in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways.
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miR-7通过靶向EGFR/IGF-1R/CRAF并抑制MAPK和PI3K/AKT信号通路逆转黑色素瘤对BRAFi的耐药性
DOI：
10.18632/oncotarget.10669
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发表时间：
2016-08-16
期刊：
影响因子：
--
通讯作者：
Tao J
中科院分区：
文献类型：
--
作者：
Sun X;Li J;Sun Y;Zhang Y;Dong L;Shen C;Yang L;Yang M;Li Y;Shen G;Tu Y;Tao J
MicroRNA (miRNA) 是各种难治性肿瘤的有吸引力的治疗靶点。然而，黑色素瘤中 miRNA 与 BRAF 抑制剂耐药性之间的关联仍有待阐明。我们使用微阵列分析来全面研究维莫非尼耐药 (VemR) A375 黑色素瘤细胞与亲代 A375 黑色素瘤细胞相关的 miRNA 表达谱。 MicroRNA-7 (miR-7) 被确定为 VemR A375 黑色素瘤细胞中下调最显着的 miRNA。我们还发现 miR-7 在 Mel-CVR 细胞（维莫非尼耐药 Mel-CV 黑色素瘤细胞）中下调。重建 miR-7 表达可以逆转两种细胞对维莫非尼的耐药性。我们发现表皮生长因子受体 (EGFR)、胰岛素样生长因子-1 受体 (IGF-1R) 和 CRAF 在 VemR A375 黑色素瘤细胞中过度表达。引入miR-7模拟物可以显着降低VemR A375黑色素瘤细胞中EGFR、IGF-1R和CRAF的表达，并进一步抑制MAPK和PI3K/AKT通路的激活。此外，在转染 miR-7 模拟物的体内鼠 VemR A375 黑色素瘤模型中，肿瘤生长受到抑制。总的来说，我们的研究表明，miR-7 可以逆转某些维莫非尼耐药黑色素瘤细胞系对 BRAF 抑制剂的耐药性。它可以推进该领域的发展，并为黑色素瘤中 BRAF 抑制剂耐药性的进一步研究提供基础。
MicroRNAs (miRNAs) are attractive therapeutic targets for various therapy-resistant tumors. However, the association between miRNA and BRAF inhibitor resistance in melanoma remains to be elucidated. We used microarray analysis to comprehensively study the miRNA expression profiling of vemurafenib resistant (VemR) A375 melanoma cells in relation to parental A375 melanoma cells. MicroRNA-7 (miR-7) was identified to be the most significantly down-regulated miRNA in VemR A375 melanoma cells. We also found that miR-7 was down-regulated in Mel-CVR cells (vemurafenib resistant Mel-CV melanoma cells). Reestablishment of miR-7 expression could reverse the resistance of both cells to vemurafenib. We showed that epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R) and CRAF were over-expressed in VemR A375 melanoma cells. Introduction of miR-7 mimics could markedly decrease the expressions of EGFR, IGF-1R and CRAF and further suppressed the activation of MAPK and PI3K/AKT pathway in VemR A375 melanoma cells. Furthermore, tumor growth was inhibited in an in vivo murine VemR A375 melanoma tumor model transfected with miR-7 mimics. Collectively, our study demonstrated that miR-7 could reverse the resistance to BRAF inhibitors in certain vemurafenib resistant melanoma cell lines. It could advance the field and provide the basis for further studies in BRAF inhibitor resistance in melanoma.