Interferon Gamma Receptor 2 Collaborates With Circular RNA/MicroRNA to Modulate Programmed Cell Death-Ligand 1 Levels in Nasopharyngeal Carcinoma

Abstract

Background: The effectiveness of immune checkpoint therapy highlights the need to understand abnormal programmed cell death protein-1 (PD-1) expression in nasopharyngeal carcinoma (NPC), especially when treatments fail, or resistance develops. Interferon gamma (IFN-γ) signaling is crucial for regulating programmed cell death-ligand 1 (PD-L1) expression. Our study focuses on interferon gamma receptor 2 (IFNGR2), an essential part of the IFN-γ pathway, and its impact on malignant traits in NPC.

Methods: The expression levels of IFNGR2 and PD-L1 were accessed using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). To understand the cellular phenotypic effects, small interfering RNA (siRNA)/short hairpin RNA (shRNA) knockdown techniques were used to evaluate cell viability, clonogenic survival, migration and invasion, immunohistochemistry, and tumor formation assays. The relationship between IFNGR2 and microRNAs (miRNAs)/circular RNAs (circRNAs) will be verified using methods such as circRNA stability assay, rescue, and dual-luciferase reporter assay.

Results: IFNGR2 was significantly overexpressed in NPC, and its expression positively correlated with PD-L1 levels. This overexpression contributed to increased cell proliferation, migration, invasion, clonogenicity, and tumor growth. Additionally, we identified an oncogenic circular RNA, circ_001377, and uncovered a novel mechanism by which upregulation of circ_001377 competitively bound to miR-498-3p. This interaction reduced miR-498-3p’s ability to target IFNGR2. As a result, the diminished miR-498-3p led to increased IFNGR2 expression, which subsequently activated the IFN-γ signaling pathway and drove abnormal PD-L1 expression.

Conclusions: IFNGR2 is an oncogenic factor in NPC. The circ_001377/miR-498-3p interaction drives IFNGR2 upregulation and PD-L1 overexpression, suggesting that targeting this axis could improve therapeutic outcomes.