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Oncoimmunology. 2016 Oct 14;5(12):e1242547. doi: 10.1080/2162402X.2016.1242547. eCollection 2016.

Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling.

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Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University , Sapporo, Hokkaido, Japan.
Division of Functional immunology, Institute for Genetic Medicine, Hokkaido University , Sapporo, Hokkaido, Japan.
ASUBIO pharma Co.,Ltd. Kobe, Hyogo, Japan.
Department of Anti-aging and Genomics, Ehime University Proteo-Medicine Research Center , To-on, Ehime, Japan.


Esophageal cancer-related gene 4 (Ecrg4), a hormone-like peptide, is thought to be a tumor suppressor, however, little is known about the mechanism of how Ecrg4 suppresses tumorigenesis. Here, we show that the ecrg4 null glioma-initiating cell (GIC) line, which was generated from neural stem cells of ecrg4 knockout (KO) mice, effectively formed tumors in the brains of immunocompetent mice, whereas the transplanted ecrg4 wild type-GIC line GIC(+/+) was frequently eliminated. This was caused by host immune system including adaptive T cell responses, since depletion of CD4+, CD8+, or NK cells by specific antibodies in vivo recovered tumorigenicity of GIC(+/+). We demonstrate that Ecrg4 fragments, amino acid residues 71-132 and 133-148, which are produced by the proteolitic cleavage, induced the expression of pro-inflammatory cytokines in microglia in vitro. Moreover, blockades of type-I interferon (IFN) signaling in vivo, either depleting IFN-α/β receptor 1 or using stat1 KO mice, abrogated the Ecrg4-dependent antitumor activity. Together, our findings indicate a major antitumor function of Ecrg4 in enhancing host immunity via type-I IFN signaling, and suggest its potential as a clinical candidate for cancer immunotherapy.


Ecrg4; glioma; immunosurveillance; microglia; type-I IFN

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