| First Author | Luo X | Year | 2024 |
| Journal | Int Immunopharmacol | Volume | 127 |
| Pages | 111376 | PubMed ID | 38113691 |
| Mgi Jnum | J:344328 | Mgi Id | MGI:7575583 |
| Doi | 10.1016/j.intimp.2023.111376 | Citation | Luo X, et al. (2024) SRSF10 facilitates HCC growth and metastasis by suppressing CD8(+)T cell infiltration and targeting SRSF10 enhances anti-PD-L1 therapy. Int Immunopharmacol 127:111376 |
| abstractText | 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/CCl(4) model, Srsf10( big up tri, openhep) model, and Srsf10(HepOE) 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 IFNalpha/gamma signaling pathway and promoted the HIF1alpha-mediated up-regulation of PD-L1 in HCC. Hepatocyte-specific SRSF10 deficiency alleviated the DEN/CCl(4)-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 IFNalpha/gamma signaling pathway and induced the HIF1alpha signal mediated PD-L1 up-regulation. Targeting SRSF10 combined with anti-PD-L1 therapy showed promising efficacy. |
