Whole Body Melanoma Transcriptome Response in Medaka.
Whole Body Melanoma Transcriptome Response in Medaka.
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DOI：
10.1371/journal.pone.0143057
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Warren WC
中科院分区：
文献类型：
--
作者：
Schartl M;Shen Y;Maurus K;Walter R;Tomlinson C;Wilson RK;Postlethwait J;Warren WC
恶性黑色素瘤的发病率每年持续增加，许多复发病例的生存预后较差。为了扭转这一趋势，需要采取全身反应措施来发现原发性和继发性恶性肿瘤的协同路径。几种鱼类提供了极好的黑色素瘤模型，因为鱼类和人类黑色素细胞都出现在表皮中，并且鱼类和人类色素细胞肿瘤共享保守的基因表达特征。我们首次检查了全身转录组对侵袭性黑色素瘤的反应，作为使用转录组分析在青鳉（Oryzias latipes）模型中筛选药物的前奏。我们从对照鱼和黑色素瘤鱼的全身 RNA 分离物中生成了 RNA-seq 数据。经过差异表达测试后，黑色素瘤鱼和对照鱼的全身转录组中有 396 个基因的表达存在显着差异（调整后的 p 值<0.02）；其中 379 个基因与人类直系同源基因相匹配，其中 233 个具有注释的人类基因符号，14 个匹配基因包含不同复发水平的人类黑色素瘤中推定的有害变异。对显着富集的详细规范途径评估显示得分最高的途径是抗原呈递，但也包括预期的黑素细胞发育和色素沉着信号传导途径。结果显示，参与免疫反应的基因显着下调，尤其是先天免疫系统。我们假设，正在发展的黑色素瘤会主动抑制身体对侵袭性恶性肿瘤做出反应的免疫系统反应，并且这种适应不良的反应会导致疾病进展，这一结果表明我们的全身转录组学方法值得进一步使用。在这些发现中，我们还观察到了人类黑色素瘤表达研究中尚未发现的新基因，并发现了已知的和新的候选药物靶点，以便在这种恶性黑色素瘤青鳉模型中进行进一步测试。
The incidence of malignant melanoma continues to increase each year with poor prognosis for survival in many relapse cases. To reverse this trend, whole body response measures are needed to discover collaborative paths to primary and secondary malignancy. Several species of fish provide excellent melanoma models because fish and human melanocytes both appear in the epidermis, and fish and human pigment cell tumors share conserved gene expression signatures. For the first time, we have examined the whole body transcriptome response to invasive melanoma as a prelude to using transcriptome profiling to screen for drugs in a medaka (Oryzias latipes) model. We generated RNA-seq data from whole body RNA isolates for controls and melanoma fish. After testing for differential expression, 396 genes had significantly different expression (adjusted p-value <0.02) in the whole body transcriptome between melanoma and control fish; 379 of these genes were matched to human orthologs with 233 having annotated human gene symbols and 14 matched genes that contain putative deleterious variants in human melanoma at varying levels of recurrence. A detailed canonical pathway evaluation for significant enrichment showed the top scoring pathway to be antigen presentation but also included the expected melanocyte development and pigmentation signaling pathway. Results revealed a profound down-regulation of genes involved in the immune response, especially the innate immune system. We hypothesize that the developing melanoma actively suppresses the immune system responses of the body in reacting to the invasive malignancy, and that this mal-adaptive response contributes to disease progression, a result that suggests our whole-body transcriptomic approach merits further use. In these findings, we also observed novel genes not yet identified in human melanoma expression studies and uncovered known and new candidate drug targets for further testing in this malignant melanoma medaka model.