Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression.
Gene expression analyses of primary melanomas reveal CTHRC1 as an important player in melanoma progression.
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DOI：
10.18632/oncotarget.7604
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发表时间：
2016-03-22
期刊：
影响因子：
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通讯作者：
Hölttä E
中科院分区：
文献类型：
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作者：
Eriksson J;Le Joncour V;Nummela P;Jahkola T;Virolainen S;Laakkonen P;Saksela O;Hölttä E
黑色素瘤因其高转移倾向和转移后对常规治疗无效而臭名昭著，而且大多数靶向治疗的反应都是短暂的。需要更好地了解黑色素瘤发生和进展背后的分子机制，以开发更有效的疗法并识别新的标记物来预测疾病行为。在这里，我们比较了良性痣、非转移性和转移性原发性黑色素瘤的基因表达谱，以确定疾病进展中的任何常见变化。我们发现了一些与炎症、血管生成和细胞外基质修饰相关的基因在转移性黑色素瘤中上调。我们选择了其中一个基因——胶原蛋白三螺旋重复序列1（CTHRC1）进行详细分析，发现CTHRC1在黑色素瘤细胞和相关成纤维细胞以及肿瘤血管内皮细胞中表达。通过 shRNA 敲低黑色素瘤细胞中的 CTHRC1 表达，可抑制其在 Transwell 实验中的迁移以及其在三维胶原蛋白和基质胶基质中的侵袭。我们还通过 CTHRC1 敲低细胞的基因表达谱阐明了 CTHRC1 可能的下游效应子。我们的分析表明，CTHRC1 与纤连蛋白和整合素 β3 受促侵袭和血管生成转录因子 NFATC2 协调调节。我们还发现 CTHRC1 是 TFGβ 和 BRAF 的靶标。这些数据强调了肿瘤基质在黑色素瘤进展中的重要性。此外，CTHRC1 被认为是黑色素瘤细胞迁移和侵袭的重要介质，与其调节因子 NFATC2、TGFβ 和 BRAF 一起提供了针对转移性黑色素瘤的有吸引力的治疗靶点。
Melanoma is notorious for its high tendency to metastasize and its refractoriness to conventional treatments after metastasis, and the responses to most targeted therapies are short-lived. A better understanding of the molecular mechanisms behind melanoma development and progression is needed to develop more effective therapies and to identify new markers to predict disease behavior. Here, we compared the gene expression profiles of benign nevi, and non-metastatic and metastatic primary melanomas to identify any common changes in disease progression. We identified several genes associated with inflammation, angiogenesis, and extracellular matrix modification to be upregulated in metastatic melanomas. We selected one of these genes, collagen triple helix repeat containing 1 (CTHRC1), for detailed analysis, and found that CTHRC1 was expressed in both melanoma cells and the associated fibroblasts, as well as in the endothelium of tumor blood vessels. Knockdown of CTHRC1 expression by shRNAs in melanoma cells inhibited their migration in Transwell assays and their invasion in three-dimensional collagen and Matrigel matrices. We also elucidated the possible down-stream effectors of CTHRC1 by gene expression profiling of the CTHRC1-knockdown cells. Our analyses showed that CTHRC1 is regulated coordinately with fibronectin and integrin β3 by the pro-invasive and -angiogenic transcription factor NFATC2. We also found CTHRC1 to be a target of TFGβ and BRAF. These data highlight the importance of tumor stroma in melanoma progression. Furthermore, CTHRC1 was recognized as an important mediator of melanoma cell migration and invasion, providing together with its regulators—NFATC2, TGFβ, and BRAF—attractive therapeutic targets against metastatic melanomas.