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.
Highlights
Chemokines are a family of low molecular weight (8-10 kDa) pro-inflammatory cytokines, which bind to chemokine receptors and sustain the migration of various leukocytes such as neutrophils, lymphocytes, monocytes, and dendritic cells
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
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
Summary
Chemokines are a family of low molecular weight (8-10 kDa) pro-inflammatory cytokines, which bind to chemokine receptors and sustain the migration of various leukocytes such as neutrophils, lymphocytes, monocytes, and dendritic cells. These molecules can be secreted by tumors, the adjacent stroma, and inflammatory cells, and play important roles in the occurrence and development of cancers [1]. They induce diverse cellular processes in tumors, such as proliferation, apoptosis and metastasis, by binding to the chemokine receptors [2]. CCL20-CCR6 interaction stimulates the epithelial-mesenchymal transition (EMT) and metastasis of colorectal cancer via the PI3K/AKTERK1/2 signaling axis [7] and AKT signaling [12, 13] and promotes proliferation and invasion
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