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MicroRNAs miRNAs have been


shown to regulate various processes of metastasis so Tavazoie and col-leagues investigated their role in melanoma metastasisPencheva et al compared small RNA profiles of lung metastatic human melanoma

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Document on Subject : "MicroRNAs miRNAs have been"— Transcript:

1 MicroRNAs (miRNAs) have been shown to r
MicroRNAs (miRNAs) have been shown to regulate various processes of metastasis, so Tavazoie and col - leagues investigated their role in melanoma metastasis. Pencheva et al . compared small RNA profiles of lung metastatic human melanoma cell lines with their poorly metastatic parental cell lines (MeWo and A375 cells) and found that four miRNAs were significantly over expressed in the derivative cell lines compared with the parental cell lines. Overexpression of three of these miRNAs, miR-199a-5p, miR-1908 and miR-199a-3p, individually in MeWo cells increased lung colonization when the cells were injected into the tail veins of nude mice. Importantly, pri - mary tumour growth was unaffected when the miRNAs were overexpressed, indicating that they have a role in driv - ing metastasis. Furthermore, miRNA profiling of 71 human primary melanoma samples revealed that the expression of miR-199a-5p, miR-1908 and miR-199a-3p was significantly increased in patients who subsequently So, how do these miRNAs drive metastasis? Overexpression of miR-199a-5p, miR-1908 or miR-199a-3p in MeWo cells increased their invasive capacity in Matrigel and their ability to recruit endothelial cells in vitro , whereas knockdown of these miRNAs in two metastatic derivative cell lines, MeWo-LM2 and A375-LM3, had the opposite effect. Furthermore, lung metastases that formed from tail vein injection of MeWo-LM2 and A375-LM3 cells in which each of the miRNAs was knocked down had reduced endothelial cell content and The authors reasoned that as altering the expression of each of the miRNAs conferred similar pheno - types, they may have overlapping tar - get mRNAs. Indeed, they found that the expression of apolipo proteinE (APOE) was suppressed by miR-199a-5p and miR-1908, and the expression of DNAJA4 was suppressed by miR-199a-3p, miR-199a-5p and miR-1908. Moreover, APOE and DNAJA4 knockdown increased the ability of MeWo cells to invade Matrigel and recruit endothelial cells in vitro , indicating that these miRNAs drive melanoma metastasis by suppressing these targets. that DNAJA4, a heat shock protein, regulated the expression of APOE such that DNAJA4 overexpression increased the levels of both APOE mRNA and secreted APOE protein. Furthermore, treating MeWo cells with recombinant APOE prevented the increased cell invasion and endothelial recruitment that resulted from DNAJA4 knockdown. Therefore, APOE seems to be the target of three metastasis-promoting miRNAs, and by using various tissue microarray data sets, the authors confirmed that APOE expression was reduced in human melanoma metastases. How does APOE suppress melanoma metastasis? Consistent with APOE being a secreted protein, the authors found that injecting MeWo-LM2 cells that had been cul - tured with recombinant APOE signifi - cantly reduced metastatic colonization in wild-type and Apoe / mice, indicat - ing that melanoma cell-derived APOE systemically suppresses metastasis. Next, the authors knocked down the four APOE receptors in MeWo-LM2 cells and found that knockdown of LRP1 increased Matrigel invasion and knockdown of LRP8 on endothelial cells further increased their recruit - ment to MeWo-LM2 cells. Finally, injection of antisense locked nucleic acids to the three miRNAs reduced lung colonization of tail vein-injected MeWo-LM2 cells in nude mice, indicating that this pathway may have therapeutic potential. In summary, the authors have identified three miRNAs (miR- 199a-5p, miR-1908 and miR-199a-3p) that, through downregulation of DNAJA4 and APOE, abrogate metastasis suppressor pathways that are mediated by APOELRP1 in melanoma cells and by APOELRP8 in endothelial cells. Gemma K. Alderton ORIGINAL RESEARCH PAPER Pencheva, N. et al . Convergent multi-miRNA targeting of ApoE drives angiogenesis. Cell 8 Nov 2012 (doi:10.1016/ j.cell.2012.10.028) melanoma cell- derived APOE systemically suppresses metastasis David Harrington METASTASIS Converging targets RESEARCH HIGHLIGHTS NATURE REVIEWS | CANCER VOLUME 12 | DECEMBER 2012 2012 Macmillan Publishers Limited. All rights reserved