Axl acts as a tumor suppressor by regulating LIGHT expression in T lymphoma

Axl is an oncogenic receptor tyrosine kinase that plays a role in many cancers. LIGHT (Lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells) is a ligand that induces robust anti-tumor immunity by enhancing the recruitment and activati...

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Bibliographic Details
Published in:Oncotarget 2017-03, Vol.8 (13), p.20645-20655
Main Authors: Lee, Eun-Hee, Kim, Eun-Mi, Ji, Kon-Young, Park, A-Reum, Choi, Ha-Rim, Lee, Hwa-Youn, Kim, Su-Man, Chung, Byung Yeoup, Park, Chul-Hong, Choi, Hyo Jin, Ko, Young-Hyeh, Bai, Hyoung-Woo, Kang, Hyung-Sik
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Electrophoretic Mobility Shift Assay
Flow Cytometry
Fluorescent Antibody Technique
Gene Expression Regulation, Neoplastic - physiology
Genes, Tumor Suppressor - physiology
Humans
Lymphoma, T-Cell - metabolism
Lymphoma, T-Cell - pathology
Mice
Mice, Inbred C57BL
Mutagenesis, Site-Directed
Polymerase Chain Reaction
Proto-Oncogene Proteins - metabolism
Receptor Protein-Tyrosine Kinases - metabolism
Research Paper: Immunology
Tumor Necrosis Factor Ligand Superfamily Member 14 - metabolism
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Summary:Axl is an oncogenic receptor tyrosine kinase that plays a role in many cancers. LIGHT (Lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells) is a ligand that induces robust anti-tumor immunity by enhancing the recruitment and activation of effector immune cells at tumor sites. We observed that mouse EL4 and human Jurkat T lymphoma cells that stably overexpressed Axl also showed high expression of LIGHT. When Jurkat-Axl cells were treated with Gas6, a ligand for Axl, LIGHT expression was upregulated through activation of the PI3K/AKT signaling pathway and transcriptional induction by Sp1. The lytic activity of cytotoxic T lymphocytes and natural killer cells was enhanced by EL4-Axl cells. In addition, tumor volume and growth were markedly reduced due to enhanced apoptotic cell death in EL4-Axl tumor-bearing mice as compared to control mice. We also observed upregulated expression of CCL5 and its receptor, CCR5, and enhanced intratumoral infiltration of cytotoxic T lymphocytes and natural killer cells in EL4-Axl-bearing mice as compared to mock controls. These data strongly suggested that Axl exerts novel tumor suppressor effects by inducing upregulation of LIGHT in the tumor microenvironment of T lymphoma.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.15830