IFNγ induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV-positive gastric carcinoma

Ji Wook Moon, Su Kang Kong, Byung Soo Kim, Hyun Ji Kim, Hyangsoon Lim, Kyeonga Noh, Younghye Kim, Jung-Woo Choi, Ju-Han Lee, Young Sik Kim

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Abstract

Programmed death-ligand 1 (PD-L1) acts as an immune checkpoint inhibitor in various cancers. PD-L1 is known to be more frequently expressed in EBV (+) gastric cancer (GC). However, the mechanisms underlying the regulation of PD-L1 expression in EBV (+) GC remain unclear. We investigated the basal and inducible PD-L1 expressions in GC cells. PD-L1 expression was upregulated upon treatment with IFNγ in both EBV (-) and EBV (+) GC cells. Upon stimulation with the same concentration of IFNγ for 24 h, EBV (+) SNU-719 cells showed dramatically higher PD-L1 expression levels by activating JAK2/STAT1/IRF-1 signaling than those of EBV (-) AGS cells. PD-L1 promoter assays, chromatin immunoprecipitation, and electrophoretic mobility shift assays revealed that IFNγ-inducible PD-L1 overexpression is primarily mediated by the putative IRF-1α site of the PD-L1 promoter in EBV (+) SNU-719 cells. Moreover, EBNA1 knockdown reduced both constitutive and IFNγ-inducible PD-L1 promoter activity by decreasing the transcript and protein levels of JAK2 and subsequently STAT1/IRF-1/PD-L1 signaling. EBNA1 is suggested to be moderately enhance both constitutive and IFNγ-inducible PD-L1 expression in EBV (+) GC cells. Thus, the signaling proteins and EBNA1 that regulate PD-L1 expression are potential therapeutic targets in EBV (+) GC.

Original languageEnglish
Article number17810
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

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Human Herpesvirus 4
Stomach
Ligands
Carcinoma
Stomach Neoplasms
Chromatin Immunoprecipitation
Electrophoretic Mobility Shift Assay
Proteins

ASJC Scopus subject areas

  • General

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IFNγ induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV-positive gastric carcinoma. / Moon, Ji Wook; Kong, Su Kang; Kim, Byung Soo; Kim, Hyun Ji; Lim, Hyangsoon; Noh, Kyeonga; Kim, Younghye; Choi, Jung-Woo; Lee, Ju-Han; Kim, Young Sik.

In: Scientific Reports, Vol. 7, No. 1, 17810, 01.12.2017.

Research output: Contribution to journalArticle

Moon, Ji Wook ; Kong, Su Kang ; Kim, Byung Soo ; Kim, Hyun Ji ; Lim, Hyangsoon ; Noh, Kyeonga ; Kim, Younghye ; Choi, Jung-Woo ; Lee, Ju-Han ; Kim, Young Sik. / IFNγ induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV-positive gastric carcinoma. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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abstract = "Programmed death-ligand 1 (PD-L1) acts as an immune checkpoint inhibitor in various cancers. PD-L1 is known to be more frequently expressed in EBV (+) gastric cancer (GC). However, the mechanisms underlying the regulation of PD-L1 expression in EBV (+) GC remain unclear. We investigated the basal and inducible PD-L1 expressions in GC cells. PD-L1 expression was upregulated upon treatment with IFNγ in both EBV (-) and EBV (+) GC cells. Upon stimulation with the same concentration of IFNγ for 24 h, EBV (+) SNU-719 cells showed dramatically higher PD-L1 expression levels by activating JAK2/STAT1/IRF-1 signaling than those of EBV (-) AGS cells. PD-L1 promoter assays, chromatin immunoprecipitation, and electrophoretic mobility shift assays revealed that IFNγ-inducible PD-L1 overexpression is primarily mediated by the putative IRF-1α site of the PD-L1 promoter in EBV (+) SNU-719 cells. Moreover, EBNA1 knockdown reduced both constitutive and IFNγ-inducible PD-L1 promoter activity by decreasing the transcript and protein levels of JAK2 and subsequently STAT1/IRF-1/PD-L1 signaling. EBNA1 is suggested to be moderately enhance both constitutive and IFNγ-inducible PD-L1 expression in EBV (+) GC cells. Thus, the signaling proteins and EBNA1 that regulate PD-L1 expression are potential therapeutic targets in EBV (+) GC.",
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