Abstract
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.
Highlights
Activating mutations in BRAF are found in a large proportion of metastatic melanomas [1]
We showed that epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R) and CRAF were over-expressed in vemurafenib resistant (VemR) A375 melanoma cells
We found that epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R) and CRAF were overexpressed in VemR A375 melanoma cells. miR-7 could decrease the expressions of EGFR, IGF-1R and CRAF and further suppressed the activation of MAPK and PI3K/AKT pathways in VemR A375 melanoma cells
Summary
Activating mutations in BRAF are found in a large proportion of metastatic melanomas [1]. Selective small molecular inhibitors targeting this key genetic mutation, e.g., BRAF inhibitors (BRAFi) vemurafenib and dabrafenib, have demonstrated high initial responses [2,3,4], acquired drug resistance is almost universal and relapse occurs in almost all patients [5]. Upregulating genetic mutations in PI3K/AKT pathway as second core resistance mechanism play an important role in acquired BRAFi resistance [9, 10]. Understanding how genetic mutations shape the resistance to BRAFi and exploring how gene modulations (e.g., RNA interference with microRNA and small interfering RNA) reverse BRAFi resistance will become more important. MicroRNA (miRNA), a 20-22 nucleotide noncoding RNA, is capable of modulating gene expression through imperfect base-pairing with specific sequences in the 3’ untranslated regions (UTRs) of target mRNAs, causing either mRNA degradation or translation inhibition [11]. Limited miRNA-related research on BRAFi resistance in melanoma has been carried out with few publications in this field
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