Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden.
Mol Oncol. 2014 Dec;8(8):1365-78. doi: 10.1016/j.molonc.2014.05.008. Epub 2014 May 27.
Extensive research has demonstrated a tumor-promoting role of increased WNT5A expression in malignant melanoma. However, very little light has been shed upon how WNT5A expression is up-regulated in melanoma. A potential regulator of WNT5A expression is the pro-inflammatory cytokine Interleukin (IL)-6, which shares the ability of WNT5A to increase melanoma cell invasion. Here, we investigate whether IL-6 can promote melanoma cell motility through an increased expression of WNT5A. We clearly demonstrate that the WNT5A-antagonistic peptide Box5 could inhibit IL-6-induced melanoma cell migration and invasion. Furthermore, IL-6 stimulation of the human melanoma cell lines HTB63 and A375 increased the expression of WNT5A in a dose-dependent manner. To identify the signaling mechanism responsible for this up-regulation, we explored the involvement of the three main signals induced by IL-6; STAT3, Akt and ERK 1/2. Of these, only STAT3 was activated by IL-6 in the melanoma cell lines tested. However, the STAT3 inhibitor S3I-201 failed to inhibit IL-6-induced WNT5A up-regulation in HTB63 and A375 cells. Nor did STAT3 siRNA silencing affect the expression of WNT5A. In search of an alternative signaling mechanism, we detected IL-6-induced activation of p38-MAPK in HTB63 and A375 cells. The p38-MAPK inhibitor SB203580 abolished the IL-6-induced WNT5A up-regulation and blocked IL-6-induced melanoma cell invasion. The latter effect could be rescued by the addition of recombinant WNT5A. Notably, immunoprecipitation analysis revealed that only the p38α-MAPK isoform was activated by IL-6, and subsequent siRNA silencing of p38α-MAPK abolished the IL-6-induced up-regulation of WNT5A. Taken together, we demonstrate a novel link between the two melanoma pro-metastatic agents IL-6 and WNT5A explaining how IL-6 can increase melanoma cell invasion and thus promote the metastatic process. This finding provides a basis for future therapeutic intervention of melanoma progression.
大量研究表明，WNT5A 表达增加在恶性黑色素瘤中具有促进肿瘤的作用。然而，关于黑色素瘤中 WNT5A 表达如何上调的研究却很少。WNT5A 表达的一个潜在调节剂是促炎细胞因子白细胞介素（IL）-6，它与 WNT5A 具有增加黑色素瘤细胞侵袭的能力。在这里，我们研究了 IL-6 是否可以通过增加 WNT5A 的表达来促进黑色素瘤细胞的运动性。我们清楚地表明，WNT5A 拮抗剂 Box5 可以抑制 IL-6 诱导的黑色素瘤细胞迁移和侵袭。此外，IL-6 刺激人黑色素瘤细胞系 HTB63 和 A375 以剂量依赖的方式增加 WNT5A 的表达。为了确定负责这种上调的信号机制，我们探讨了 IL-6 诱导的三种主要信号的参与；STAT3、Akt 和 ERK1/2。在测试的黑色素瘤细胞系中，只有 STAT3 被 IL-6 激活。然而，STAT3 抑制剂 S3I-201 未能抑制 HTB63 和 A375 细胞中 IL-6 诱导的 WNT5A 上调。STAT3 siRNA 沉默也不影响 WNT5A 的表达。在寻找替代信号机制时，我们检测到 HTB63 和 A375 细胞中 IL-6 诱导的 p38-MAPK 激活。p38-MAPK 抑制剂 SB203580 消除了 IL-6 诱导的 WNT5A 上调，并阻断了 IL-6 诱导的黑色素瘤细胞侵袭。后者的作用可以通过添加重组 WNT5A 来挽救。值得注意的是，免疫沉淀分析表明，只有 p38α-MAPK 同工型被 IL-6 激活，随后 p38α-MAPK 的 siRNA 沉默消除了 IL-6 诱导的 WNT5A 上调。总之，我们证明了两种黑色素瘤促转移剂 IL-6 和 WNT5A 之间的新联系，解释了 IL-6 如何增加黑色素瘤细胞侵袭并因此促进转移过程。这一发现为黑色素瘤进展的未来治疗干预提供了依据。
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