Disruption of CCL20-CCR6 interaction inhibits metastasis of advanced cutaneous T-cell lymphoma.
Disruption of CCL20-CCR6 interaction inhibits metastasis of advanced cutaneous T-cell lymphoma.
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DOI：
10.18632/oncotarget.6916
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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：
Tagawa H
中科院分区：
文献类型：
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作者：
Ikeda S;Kitadate A;Ito M;Abe F;Nara M;Watanabe A;Takahashi N;Miyagaki T;Sugaya M;Tagawa H
我们最近证实趋化因子受体CCR6及其配体CCL20的上调导致晚期皮肤T细胞淋巴瘤(CTCL)细胞的转移，提示CCL20-CCR6相互作用参与了启动CTCL细胞转移的过程。在这项研究中，我们确定了这种相互作用在转移性CTCL细胞中是否起作用。我们首先证明了在原发CTCL的进展过程中STAT3的表达增加。在CTCL细胞中，STAT3被自发激活并介导CCL20的转录。接下来，为了确定瞬时敲除STAT3、CCL20或CCR6或抗CCL20中和抗体(中和CCL20抗体)是否会降低CTCL细胞的迁移能力，我们进行了体外迁移实验。所有处理均降低了CTCL细胞的营养依赖性迁移活性。值得注意的是，用中和CCL20抗体处理降低了细胞的迁移能力，而不减少CCL20和CCR6的表达。这表明CCL20-CCR6相互作用实际上在转移性CTCL细胞中起作用。最后，为了检测CCL20抗体的体内中和效果，我们使用了接种CTCL细胞的NOD/SHI-SCID IL-2γNUL小鼠。这些小鼠被认为是由于CTCL细胞转移到多个器官而死亡。然而，给予中和CCL20抗体显著延长了移植小鼠的存活时间。这些结果提示，STAT3/CCL20/CCR6级联的自动激活参与了CTCL的发生，阻断CCL20-CCR6的相互作用可能是治疗晚期CTCL的关键策略。
We recently demonstrated that upregulation of a chemokine receptor CCR6 and its ligand CCL20 led to metastasis of advanced cutaneous T-cell lymphoma (CTCL) cells, suggesting the involvement of CCL20-CCR6 interaction in initiating CTCL cell metastasis. In this study, we determined whether this interaction is functional in metastatic CTCL cells. We first demonstrated increased STAT3 expression during the progression of primary CTCL. STAT3 was spontaneously activated and mediated the transcription of CCL20 in CTCL cell lines. Next, to determine whether the transient knockdown of STAT3, CCL20, or CCR6 or treatment with neutralizing antibody against CCL20 (neutralizing CCL20 antibody) could reduce the migration ability of CTCL cells, we conducted an in vitro migration assay. All treatments reduced the nutrition-dependent migration activity of CTCL cells. Notably, treatment with neutralizing CCL20 antibody reduced the migration ability of the cells without decreasing the expression of CCL20 and CCR6. This demonstrated that the CCL20-CCR6 interaction is actually functional in metastatic CTCL cells. Finally, to examine the in vivo effect of neutralizing CCL20 antibody, we used NOD/Shi-scid IL-2γnul mice inoculated with CTCL cells. These mice were expected to die due to metastasis of CTCL cells into multiple organs. However, administration of neutralizing CCL20 antibody significantly prolonged the survival of the xenografted mice. These findings suggested that automatic activation of the STAT3/CCL20/CCR6 cascade was involved in CTCL lymphomagenesis and that disruption of CCL20-CCR6 interaction could be a key therapeutic strategy against advanced CTCL.