SRSF10 facilitates HCC growth and metastasis by suppressing CD8+T cell infiltration and targeting SRSF10 enhances anti-PD-L1 therapy.
Int Immunopharmacol
; 127: 111376, 2024 Jan 25.
Article
em En
| MEDLINE
| ID: mdl-38113691
ABSTRACT
BACKGROUND AND AIMS:
RNA splicing is an essential step in regulating the gene posttranscriptional expression. Serine/arginine-rich splicing factors (SRSFs) are splicing regulators with vital roles in various tumors. Nevertheless, the expression patterns and functions of SRSFs in hepatocellular carcinoma (HCC) are not fully understood.METHODS:
Flow cytometry and immunofluorescent staining were used to determine the CD8+T cell infiltration. Orthotopic HCC model, lung metastasis model, DEN/CCl4 model, Srsf10â³hep model, and Srsf10HepOE model were established to evaluate the role of SRSF10 in HCC and the efficacy of combination treatment.RESULTS:
SRSF10 was one of the most survival-relevant genes among SRSF members and was an independent prognostic factor for HCC. SRSF10 facilitated HCC growth and metastasis by suppressing CD8+T cell infiltration. Mechanistically, SRSF10 down-regulated the p53 protein by preventing the exon 6 skipping (exon 7 in mouse) mediated degradation of MDM4 transcript, thus inhibiting CD8+T cell infiltration. Elimination of CD8+T cells or overexpression of MDM4 removed the inhibitory role of SRSF10 knockdown in HCC growth and metastasis. SRSF10 also inhibited the IFNα/γ signaling pathway and promoted the HIF1α-mediated up-regulation of PD-L1 in HCC. Hepatocyte-specific SRSF10 deficiency alleviated the DEN/CCl4-induced HCC progression and metastasis, whereas hepatocyte-specific SRSF10 overexpression deteriorated these effects. Finally, SRSF10 knockdown enhanced the anti-PD-L1-mediated anti-tumor activity.CONCLUSIONS:
SRSF10 promoted HCC growth and metastasis by repressing CD8+T cell infiltration mediated by the MDM4-p53 axis. Furthermore, SRSF10 suppressed the IFNα/γ signaling pathway and induced the HIF1α signal mediated PD-L1 up-regulation. Targeting SRSF10 combined with anti-PD-L1 therapy showed promising efficacy.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
/
Neoplasias Hepáticas
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article