Mutated MITF-E87R in Melanoma Enhances Tumor Progression via S100A4.
Mutated MITF-E87R in Melanoma Enhances Tumor Progression via S100A4.
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黑色素瘤中突变的 MITF-E87R 通过 S100A4 促进肿瘤进展。
DOI：
10.1016/j.jid.2018.03.1524
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Samuels,Yardena
中科院分区：
文献类型：
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作者：
Nordlinger,Alice;Dror,Shani;Elkahloun,Abdel;DelRio,Justine;Stubbs,Elisa;Golan,Tami;Malcov,Hagar;Pricket,ToddD;Cronin,JuliaC;Parikh,Shivang;Labes,Sapir;Thomas,Laetitia;Yankovitz,Gal;Tabach,Yuval;Levy,Carmit;Samuels,Yardena
黑色素瘤是一种黑色素细胞起源的肿瘤，是最致命的皮肤癌类型，发病率正在增加。在编码黑素细胞谱系主调控因子MITF的基因中发现了一些家族性和体细胞突变；然而，这些突变的mitf变异的肿瘤机制大多是未知的。在这里，通过对表达突变mitf的细胞的转录组进行无偏分析，我们发现钙结合蛋白S100A4是MITF-E87R的下游靶点。通过使用野生型和突变型mitf黑色素瘤系，我们发现内源性野生型和MITF-E87R变体都占据了100a4启动子。值得注意的是，野生型MITF抑制了ess100a4的表达，而MITF- e87r激活了其转录。野生型和突变型MITF的相反作用导致相反的细胞表型，因为与野生型MITF活性相比，MITF- e87r通过S100A4增强了侵袭性并降低了粘附性。最后，我们发现s100a4表达改变的黑色素瘤患者预后较差。这些数据表明，由于MITF点突变导致的MITF转录活性从抑制到激活s100a4的变化会削弱黑色素瘤的侵袭能力。这些数据为转移性黑色素瘤的诊断和治疗提供了新的机会。
Melanoma, a melanocyte origin neoplasm, is the most lethal type of skin cancer, and incidence is increasing. Several familial and somatic mutations have been identified in the gene encoding the melanocyte lineage master regulator,MITF; however, the neoplastic mechanisms of these mutantMITFvariants are mostly unknown. Here, by performing unbiased analysis of the transcriptomes in cells expressing mutantMITF, we identified calcium-binding protein S100A4 as a downstream target of MITF-E87R. By using wild-type and mutantMITFmelanoma lines, we found that both endogenous wild-type and MITF-E87R variants occupy theS100A4promoter. Remarkably, whereas wild-type MITF repressesS100A4expression, MITF-E87R activates its transcription. The opposite effects of wild-type and mutant MITF result in opposing cellular phenotypes, because MITF-E87R via S100A4 enhanced invasion and reduced adhesion in contrast to wild-type MITF activity. Finally, we found that melanoma patients with alteredS100A4expression have poor prognosis. These data show that a change in MITF transcriptional activity from repression to activation ofS100A4that results from a point mutation inMITFalters melanoma invasive ability. These data suggest new opportunities for diagnosis and treatment of metastatic melanoma.