Interplay Between Soluble CD74 and Macrophage-Migration Inhibitory Factor Drives Tumor Growth and Influences Patient Survival in Melanoma

Authors

Yasunari Fukuda
Matias A Bustos
Sung-Nam Cho
Jason Roszik
Suyeon Ryu
Victor M Lopez
Jared K Burks
Jeffrey E Lee
Elizabeth A Grimm
Dave S B Hoon
Suhendan Ekmekcioglu

Publication Date

2-4-2022

Journal

Cell Death & Disease

Abstract

Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of sCD74 was observed primarily in melanoma cell lines as well as a THP-1 line of macrophages from monocytes and primary macrophages, especially in response to interferon-γ (IFN-γ). A predominant form that showed clinical relevance was the 25-KDa sCD74, which originated from the 33-KDa isoform of CD74. The release of this sCD74 was regulated by either a disintegrin and metalloproteinase-mediated cell-surface cleavage or cysteine-protease-mediated lysosomal cleavage, depending on cell types. Both recombinant and THP-1 macrophage-released endogenous sCD74 suppressed melanoma cell growth and induced apoptosis under IFN-γ stimulatory conditions via inhibiting the MIF/CD74/AKT-survival pathway. Our findings demonstrate that the interplay between sCD74 and MIF regulates tumor progression and determines patient outcomes in advanced melanoma.

Keywords

Antigens, Differentiation, B-Lymphocyte, Cell Proliferation, Histocompatibility Antigens Class II, Humans, Interferon-gamma, Intramolecular Oxidoreductases, Macrophage Migration-Inhibitory Factors, Macrophages, Melanoma, Signal Transduction, Melanoma, Prognostic markers

Comments

This article has been corrected. See Cell Death Dis. 2022 May 2;13(5):422.

DOI

10.1038/s41419-022-04552-y

PMID

35121729

PMCID

PMC8816905

PubMedCentral® Posted Date

2-4-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes