Oncotarget

Research Papers:

Disruption of CCL20-CCR6 interaction inhibits metastasis of advanced cutaneous T-cell lymphoma

Sho Ikeda, Akihiro Kitadate, Mitsugu Ito, Fumito Abe, Miho Nara, Atsushi Watanabe, Naoto Takahashi, Tomomitsu Miyagaki, Makoto Sugaya and Hiroyuki Tagawa _

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Oncotarget. 2016; 7:13563-13574. https://doi.org/10.18632/oncotarget.6916

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Abstract

Sho Ikeda1,*, Akihiro Kitadate1,*, Mitsugu Ito1, Fumito Abe1, Miho Nara1, Atsushi Watanabe1, Naoto Takahashi1, Tomomitsu Miyagaki2, Makoto Sugaya2 and Hiroyuki Tagawa1

1 Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

2 Department of Dermatology, University of Tokyo, Tokyo, Japan

* These authors have contributed equally to this work

Correspondence to:

Hiroyuki Tagawa, email:

Keywords: CCL20, CCR6, CTCL, STAT3, IL-22

Received: September 10, 2015 Accepted: December 31, 2015 Published: January 14, 2016

Abstract

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.


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