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Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-γ

While melanoma is believed to be a highly immunogenic tumor and recent developments in immunotherapies are promising. Interferon-γ (IFN-γ) produced by immune cells plays a crucial role in tumor immune surveillance; however, it has also been reported to be pro-tumorigenic. In the current study, we fo...

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Autores principales: Tanese, Keiji, Hashimoto, Yuuri, Berkova, Zuzana, Wang, Yuling, Samaniego, Felipe, Lee, Jeffrey E., Ekmekcioglu, Suhendan, Grimm, Elizabeth A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640965/
https://www.ncbi.nlm.nih.gov/pubmed/26039541
http://dx.doi.org/10.1038/jid.2015.204
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author Tanese, Keiji
Hashimoto, Yuuri
Berkova, Zuzana
Wang, Yuling
Samaniego, Felipe
Lee, Jeffrey E.
Ekmekcioglu, Suhendan
Grimm, Elizabeth A.
author_facet Tanese, Keiji
Hashimoto, Yuuri
Berkova, Zuzana
Wang, Yuling
Samaniego, Felipe
Lee, Jeffrey E.
Ekmekcioglu, Suhendan
Grimm, Elizabeth A.
author_sort Tanese, Keiji
collection PubMed
description While melanoma is believed to be a highly immunogenic tumor and recent developments in immunotherapies are promising. Interferon-γ (IFN-γ) produced by immune cells plays a crucial role in tumor immune surveillance; however, it has also been reported to be pro-tumorigenic. In the current study, we found that IFN-γ enhances the expression of CD74, which interacts with its ligand, macrophage migration inhibitory factor (MIF), and thereby activates the PI3K/AKT pathway in melanoma, promoting tumor survival. IFN-γ increased phosphorylation of AKT Ser473 and upregulated total and cell surface expression of CD74 in human melanoma cell lines tested. CD74 was highly expressed in melanoma tissues. Moreover, the expression of CD74 on tumor cells correlated with plasma IFN-γ levels in melanoma patient samples. In our analysis of melanoma cell lines, all produced MIF constitutively. Blockade of CD74-MIF interaction reduced AKT phosphorylation and expression of pro-tumorigenic molecules, including interleukin-6, interleukin-8 and BCL-2. Inhibition of CD74-MIF interaction significantly suppressed tumor growth in the presence of IFN-γ in our xenograft mouse model. Thus, we conclude that IFN-γ promotes melanoma cell survival by regulating CD74-MIF signaling, suggesting that targeting the CD74-MIF interaction under IFN-γ–stimulatory conditions would be an effective therapeutic approach for melanoma.
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spelling pubmed-46409652016-05-01 Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-γ Tanese, Keiji Hashimoto, Yuuri Berkova, Zuzana Wang, Yuling Samaniego, Felipe Lee, Jeffrey E. Ekmekcioglu, Suhendan Grimm, Elizabeth A. J Invest Dermatol Article While melanoma is believed to be a highly immunogenic tumor and recent developments in immunotherapies are promising. Interferon-γ (IFN-γ) produced by immune cells plays a crucial role in tumor immune surveillance; however, it has also been reported to be pro-tumorigenic. In the current study, we found that IFN-γ enhances the expression of CD74, which interacts with its ligand, macrophage migration inhibitory factor (MIF), and thereby activates the PI3K/AKT pathway in melanoma, promoting tumor survival. IFN-γ increased phosphorylation of AKT Ser473 and upregulated total and cell surface expression of CD74 in human melanoma cell lines tested. CD74 was highly expressed in melanoma tissues. Moreover, the expression of CD74 on tumor cells correlated with plasma IFN-γ levels in melanoma patient samples. In our analysis of melanoma cell lines, all produced MIF constitutively. Blockade of CD74-MIF interaction reduced AKT phosphorylation and expression of pro-tumorigenic molecules, including interleukin-6, interleukin-8 and BCL-2. Inhibition of CD74-MIF interaction significantly suppressed tumor growth in the presence of IFN-γ in our xenograft mouse model. Thus, we conclude that IFN-γ promotes melanoma cell survival by regulating CD74-MIF signaling, suggesting that targeting the CD74-MIF interaction under IFN-γ–stimulatory conditions would be an effective therapeutic approach for melanoma. 2015-06-03 2015-11 /pmc/articles/PMC4640965/ /pubmed/26039541 http://dx.doi.org/10.1038/jid.2015.204 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Tanese, Keiji
Hashimoto, Yuuri
Berkova, Zuzana
Wang, Yuling
Samaniego, Felipe
Lee, Jeffrey E.
Ekmekcioglu, Suhendan
Grimm, Elizabeth A.
Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-γ
title Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-γ
title_full Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-γ
title_fullStr Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-γ
title_full_unstemmed Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-γ
title_short Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-γ
title_sort cell surface cd74-mif interactions drive melanoma survival in response to interferon-γ
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640965/
https://www.ncbi.nlm.nih.gov/pubmed/26039541
http://dx.doi.org/10.1038/jid.2015.204
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