Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma.
Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma.
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DOI：
10.18632/oncotarget.2164
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发表时间：
2014-07-30
期刊：
影响因子：
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通讯作者：
Behren A
中科院分区：
文献类型：
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作者：
Jayachandran A;Anaka M;Prithviraj P;Hudson C;McKeown SJ;Lo PH;Vella LJ;Goding CR;Cebon J;Behren A
上皮 - 间质转化（EMT）是黑色素瘤转移的一个决定性因素，在上皮细胞发生EMT时，上皮细胞会失去极性并变成可移动的间质细胞。我们比较了间质样黑色素瘤细胞和上皮样黑色素瘤细胞的基因表达特征，并确定血小板反应蛋白1（THBS1）在间质表型中高度上调。本研究探讨了转化生长因子（TGF）-β的主要生理激活因子THBS1是否参与黑色素瘤的类EMT过程。我们试图检测不同黑色素瘤表型中的表达模式，包括侵袭性、去分化、标记滞留和耐药群体，这些表型可能与类EMT过程有关。
在此我们表明，在表现出侵袭性、耐药性、标记滞留和间质表型的黑色素瘤细胞中，THBS1的表达和分泌增加，并且与参与色素沉着的基因表达降低相关。在维莫非尼耐药的黑色素瘤细胞中检测到THBS1水平升高，并且抑制THBS1可显著降低黑色素瘤细胞的化疗耐药性。值得注意的是，通过小干扰RNA（siRNA）介导的THBS1沉默以及THBS1中和抗体可减少间质样黑色素瘤细胞的侵袭，而上皮样黑色素瘤细胞中异位表达THBS1会增强侵袭。此外，THBS1的缺失抑制了黑色素瘤细胞在鸡胚神经管内的体内移动性。此外，我们在转移性黑色素瘤肿瘤活检中发现了THBS1蛋白的异常表达。这些结果表明THBS1在EMT中起作用，因此THBS1可能成为治疗黑色素瘤侵袭和耐药的新策略靶点。
Epithelial-to-mesenchymal transition (EMT), in which epithelial cells loose their polarity and become motile mesenchymal cells, is a determinant of melanoma metastasis. We compared gene expression signatures of mesenchymal-like melanoma cells with those of epithelial-like melanoma cells, and identified Thrombospondin 1 (THBS1) as highly up-regulated in the mesenchymal phenotype. This study investigated whether THBS1, a major physiological activator of transforming growth factor (TGF)-beta, is involved in melanoma EMT-like process. We sought to examine expression patterns in distinct melanoma phenotypes including invasive, de-differentiated, label-retaining and drug resistant populations that are putatively associated with an EMT-like process. Here we show that THBS1 expression and secretion was elevated in melanoma cells exhibiting invasive, drug resistant, label retaining and mesenchymal phenotypes and correlated with reduced expression of genes involved in pigmentation. Elevated THBS1 levels were detected in Vemurafenib resistant melanoma cells and inhibition of THBS1 led to significantly reduced chemoresistance in melanoma cells. Notably, siRNA-mediated silencing of THBS1 and neutralizing antibody to THBS1 reduced invasion in mesenchymal-like melanoma cells, while ectopic THBS1 expression in epithelial-like melanoma cells enhanced invasion. Furthermore, the loss of THBS1 inhibited in vivo motility of melanoma cells within the embryonic chicken neural tube. In addition, we found aberrant THBS1 protein expression in metastatic melanoma tumor biopsies. These results implicate a role for THBS1 in EMT, and hence THBS1 may serve as a novel target for strategies aimed at the treatment of melanoma invasion and drug resistance.