Induction of exportin-5 expression during melanoma development supports the cellular behavior of human malignant melanoma cells.
Induction of exportin-5 expression during melanoma development supports the cellular behavior of human malignant melanoma cells.
复制标题
DOI：
10.18632/oncotarget.11410
复制
发表时间：
2016-09-20
期刊：
影响因子：
--
通讯作者：
Bosserhoff AK
中科院分区：
文献类型：
--
作者：
Ott CA;Linck L;Kremmer E;Meister G;Bosserhoff AK
众所周知，通过microRNAs调节基因表达可以促进许多类型癌症的发展。在黑色素瘤中，miRNAs在全球范围内上调，并且已经确定了miRNA处理酶的变化。然而，对miRNA转运的错误调控在黑色素瘤中还没有得到分析。我们假设miRNA运输的变化扰乱了miRNA的加工。因此，我们调查了前miRNA转运体Exportin-5(XPO5)是否参与了黑色素瘤miRNA成熟和功能后果的改变。我们发现，与黑素细胞相比，XPO5在黑色素瘤中显著过度表达。我们发现在黑色素瘤细胞系中XPO5的mRNA稳定性增强，这可能是XPO5蛋白表达上调的原因。此外，我们发现MEK信号是黑色素瘤中XPO5表达的调节因子。XPO5在黑色素瘤细胞中的表达下调导致成熟miRNA水平下降和功能急剧变化。我们的数据表明XPO5的异常表达对于miRNAs的成熟和黑色素瘤细胞的恶性行为是重要的。我们认为XPO5在黑色素瘤中的高丰度导致了生存、增殖和转移的增强，从而支持了黑色素瘤的侵袭性。
Regulation of gene expression via microRNAs is known to promote the development of many types of cancer. In melanoma, miRNAs are globally up-regulated, and alterations of miRNA-processing enzymes have already been identified. However, mis-regulation of miRNA transport has not been analyzed in melanoma yet. We hypothesized that alterations in miRNA transport disrupt miRNA processing. Therefore, we investigated whether the pre-miRNA transporter Exportin-5 (XPO5) was involved in altered miRNA maturation and functional consequences in melanoma. We found that XPO5 is significantly over-expressed in melanoma compared with melanocytes. We showed enhanced XPO5 mRNA stability in melanoma cell lines which likely contributes to up-regulated XPO5 protein expression. In addition, we identified MEK signaling as a regulator of XPO5 expression in melanoma. Knockdown of XPO5 expression in melanoma cells led to decreased mature miRNA levels and drastic functional changes. Our data revealed that aberrant XPO5 expression is important for the maturation of miRNAs and the malignant behavior of melanoma cells. We suggest that the high abundance of XPO5 in melanoma leads to enhanced survival, proliferation and metastasis and thereby supports the aggressiveness of melanoma.