Caracterización de la vía del IFN-γ e identificación de sus miRNAs blanco en células de glioblastoma”

Abstract

El glioblastoma es un tumor cerebral altamente agresivo que se caracteriza por su rápida progresión y resistencia a tratamientos. El microambiente tumoral juega un papel crucial en esta agresividad, y el IFN-γ es una citocina clave que contribuye a ello. Al activar ciertos genes, el IFN-γ limita la respuesta inmunológica antitumoral. Además, este estudio revela que el IFN-γ aumenta la expresión de microRNAs asociados con características pro-tumorales como la proliferación y resistencia a la apoptosis. Esto sugiere que la vía del IFN-γ podría ser un objetivo terapéutico prometedor para el tratamiento del glioblastoma, al bloquear su capacidad de promover el crecimiento tumoral a través de la regulación de estos microRNAs.

ABSTRACT

Glioblastoma is the most recurrent and aggressive cancer of the central nervous system in 64 years old patients. It is a highly invasive tumor that progresses rapidly, resulting in a short lifespan of around 14 months on average. The tumor microenvironment in glioblastoma promotes its aggressiveness due to the cytokines secreted by tumor cells, microglia, and macrophages. One of the most relevant cytokines is IFN-γ; its signaling pathway activates the transcription factor STAT1 to promote IRF1 expression, another transcription factor that induces the expression of secondary genes as PD-L1, which restricts the anti-tumor activity of T cells. Nevertheless, the impact of the IFN-γ signaling at the transcriptional level is not completely known. Moreover, in glioblastoma, several miRNAs are related to proliferation, apoptosis evasion, and radioresistance, but the modulation of their expression by IFN-γ has not been studied. Therefore, this project's main interest was identifying IFN-γ-induced miRNAs associated with tumor progression. The results indicate that the IFN-γ signaling pathway elements expression is incremented in glioblastoma patient’s samples, especially in two specific points of this pathway: the IFN-γ receptor (IFNGR1 and IFNGR2 subunits) and the downstream transcription factors of this pathway, STAT1, and IRF1. The IFN-γ canonical signaling pathway activation augmented the protein levels of transcription factor IRF1 and the expression of PD-L1, one of its target genes, in the LN-18 glioblastoma cell line. Finally, a miRNA gene signature was identified that was upregulated and downregulated by IFN-γ and was also associated with its pro-tumor effect by inducing cellular responses such as cell proliferation, apoptosis evasion, and cell cycle progression, EMT, and angiogenesis. In conclusion, in this study, we demonstrated that the IFN-γ signaling pathway modulates the expression levels of a miRNA gene signature associated with its pro-tumor effect in glioblastoma cells.