miR-7 reverses the resistance to BRAFi in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways

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.

Targeted Expression of miR-7 Operated by TTF-1 Promoter Inhibited the Growth of Human Lung Cancer through the NDUFA4 Pathway

“…An increasing body of literatures documented that miR-7 could regulate the growth of lung cancer cells though various signal pathways such as the Akt and Erk pathway 27, 28, 29. Our previous work also showed that miR-7 could inhibit the proliferation and metastasis of lung cancer cells though the Akt pathway 17 .…”

Enteroendocrine Progenitor Cell–Enriched miR-7 Regulates Intestinal Epithelial Proliferation in an Xiap-Dependent Manner

“…To our knowledge, this is the first report of a miRNA enriched along the EEC lineage trajectory that exerts substantive control of enteroid growth and likely EEC abundance. Although previously miR-7 has been reported to have roles in specific cancer contexts, 17,29,30 our study is the first to our knowledge to demonstrate that miR-7 regulates intestinal growth under normal physiological conditions. It is noteworthy that modest but significant changes in miRNA expression, similar to what we show for miR-7 in this study, have been linked functionally to important phenotypes in numerous prior studies.…”

miRNAs as Key Players in the Management of Cutaneous Melanoma

“…Introduction of miR-7 decreases the expression levels of EGFR, IGF-1R, CRAF in vitro as well as in Vemurafenib-resistant cells in melanoma xenograft mice models, which indicates that EGFR, IGF-1R, and CRAF are the target genes of miR-7 that are associated with the acquired resistance to BRAFi. By decreasing the expression levels of EGFR, IGF-1R, CRAF, miR-7 could inhibit the activation of the MAPK and PI3K/AKT pathways and reverse melanoma cell resistance to BRAFi [25].…”