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首页> 外文期刊>BMC Medical Genomics >SOX5 is involved in balanced MITF regulation in human melanoma cells
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SOX5 is involved in balanced MITF regulation in human melanoma cells

机译：SOX5参与人黑素瘤细胞中MITF的平衡调节

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Background Melanoma is a cancer with rising incidence and new therapeutics are needed. For this, it is necessary to understand the molecular mechanisms of melanoma development and progression. Melanoma differs from other cancers by its ability to produce the pigment melanin via melanogenesis; this biosynthesis is essentially regulated by microphthalmia-associated transcription factor (MITF). MITF regulates various processes such as cell cycling and differentiation. MITF shows an ambivalent role, since high levels inhibit cell proliferation and low levels promote invasion. Hence, well-balanced MITF homeostasis is important for the progression and spread of melanoma. Therefore, it is difficult to use MITF itself for targeted therapy, but elucidating its complex regulation may lead to a promising melanoma-cell specific therapy. Method We systematically analyzed the regulation of MITF with a novel established transcription factor based gene regulatory network model. Starting from comparative transcriptomics analysis using data from cells originating from nine different tumors and a melanoma cell dataset, we predicted the transcriptional regulators of MITF employing ChIP binding information from a comprehensive set of databases. The most striking regulators were experimentally validated by functional assays and an MITF- promoter reporter assay. Finally, we analyzed the impact of the expression of the identified regulators on clinically relevant parameters of melanoma, i.e. the thickness of primary tumors and patient overall survival. Results Our model predictions identified SOX10 and SOX5 as regulators of MITF . We experimentally confirmed the role of the already well-known regulator SOX10. Additionally, we found that SOX5 knockdown led to MITF up-regulation in melanoma cells, while double knockdown with SOX10 showed a rescue effect; both effects were validated by reporter assays. Regarding clinical samples, SOX5 expression was distinctively up-regulated in metastatic compared to primary melanoma. In contrast, survival analysis of melanoma patients with predominantly metastatic disease revealed that low SOX5 levels were associated with a poor prognosis. Conclusion MITF regulation by SOX5 has been shown only in murine cells, but not yet in human melanoma cells. SOX5 has a strong inhibitory effect on MITF expression and seems to have a decisive clinical impact on melanoma during tumor progression.
机译：背景技术黑色素瘤是一种发病率不断上升的癌症，需要新的疗法。为此，有必要了解黑色素瘤发生和发展的分子机制。黑色素瘤与其他癌症的不同之处在于，它能够通过黑色素生成产生黑色素。这种生物合成基本上受小眼症相关转录因子（MITF）调节。 MITF调节各种过程，例如细胞周期和分化。 MITF显示出矛盾的作用，因为高水平抑制细胞增殖，而低水平则促进侵袭。因此，均衡的MITF稳态对于黑素瘤的进展和扩散很重要。因此，很难将MITF本身用于靶向治疗，但是阐明其复杂的调节作用可能会导致有希望的黑素瘤细胞特异性治疗。方法我们用一种新型的基于转录因子的基因调控网络模型系统地分析了MITF的调控。从比较转录组学分析开始，使用来自9种不同肿瘤的细胞数据和黑素瘤细胞数据集进行比较，我们利用ChIP结合信息从一组全面的数据库中预测了MITF的转录调控因子。最引人注目的调节剂已通过功能测定和MITF启动子报告基因测定进行了实验验证。最后，我们分析了已鉴定的调节子的表达对黑素瘤临床相关参数（即原发肿瘤的厚度和患者总体生存率）的影响。结果我们的模型预测确定SOX10和SOX5是MITF的调节剂。我们通过实验证实了众所周知的调节器SOX10的作用。此外，我们发现SOX5敲低导致黑色素瘤细胞中MITF上调，而SOX10的双重敲低则显示出挽救作用。两种作用均通过报告基因分析证实。关于临床样品，与原发性黑素瘤相比，SOX5表达在转移灶中明显上调。相反，对以转移性疾病为主的黑素瘤患者的生存分析表明，低SOX5水平与不良预后相关。结论SOX5对MITF的调控仅在鼠细胞中显示，而在人黑素瘤细胞中尚未显示。 SOX5对MITF表达具有很强的抑制作用，并且似乎在肿瘤进展期间对黑色素瘤具有决定性的临床影响。

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