Alternative splicing (AS) generates protein diversity and is exploited by cancer cells to drive tumor progression and resistance to many cancer therapies, including chemotherapy. SNRPA is first identified as a spliceosome-related gene that potentially modulates resistance to platinum chemotherapy. Both the knockout or the knockdown of SNRPA via CRISPR/Cas9 and shRNA techniques can reverse the resistance of cisplatin-resistant lung adenocarcinoma (LUAD) cells to cisplatin. SNRPA overexpression enhanced the resistance of cisplatin-sensitive LUAD cells. Gene Ontology (GO) analysis reveals that SNRPA is associated with DNA damage repair. Depletion of SNRPA induced ERCC1 exon 8 skipping and reduced ERCC1–XPF complex formation, whereas SNRPA overexpression exerted the opposite effect. siRNAs targeting isoforms containing ERCC1 exon 8 [ERCC1-E8 (+)] reversed SNRPA-enhanced cisplatin resistance and DNA damage repair. Furthermore, the IGF2BP protein, an m 6 A reader, and the ELAVL1 protein, an RNA stabilizer recruited by IGF2BP1, are found to bind to the SNRPA mRNA. ELAVL1 promoted cisplatin resistance, DNA repair and ERCC1-E8 (+) expression in an SNRPA-dependent manner. In a mouse xenograft model, SNRPA- KO CRISPR enhanced the sensitivity of LUAD cells to cisplatin. Overall, this study illuminates the role of SNRPA in platinum-based drug resistance, thereby providing a novel avenue to potentially enhance chemosensitivity and improve the prognosis of patients with LUAD.
Youfu Zhang,Xuyang Wang,Huaxiang Wang,Yi Jiang,Zhidan Xu,Laibang Luo
Background Elevated Small Nuclear Ribonucleoprotein Polypeptide A ( SNRPA ) can enhance tumor cell growth and proliferation in various cancers. However, rarely studies focus on the comprehensive analysis of SNRPA in hepatocellular carcinoma (HCC). Methods TCGA and GEO databases were used to analyze the mRNA expression of SNRPA in HCC. Protein expression of SNAPA was validated using immunohistochemistry. Stably transfected HCC cells were used to investigate the role of SNRPA in the progression of HCC. The functional enrichment analysis was utilized for the biological function prediction. The CIBERSORT and ssGSEA algorithms were used to evaluate the composition of the tumor microenvironment and immunocyte infiltration ratio. Results The SNRPA expression was upregulated in HCC and positively correlated with tumor stage and grade. SNRPA overexpression were independent risk factors for poor overall survival (OS) and recurrence-free survival (RFS). In patients with early-stage disease, low alpha-fetoprotein expression, and better differentiation, SNRPA still exhibited the excellent prognostic value. Knockdown of SNRPA inhibited the proliferation and migration while promoting the apoptosis of HCC cells. Higher methylation of the CpG site cg16596691 correlated with longer OS in HCC patients. Genes co-expressed with SNRPA were overexpressed in HCC and correlated with shorter OS. The GO and KEGG enrichment analysis showed that SNRPA expression was related to mRNA splicing, spliceosome signaling. GSEA demonstrated that the main enrichment pathway of SNRPA-related differential genes was spliceosome signaling, cell cycle signaling, P53 signaling pathway, T cell receptor signaling pathway, natural killer cell-mediated signaling. CIBERSORT and ssGSEA algorithm revealed that SNRPA was mainly associated with the higher proportion of CD8+T cells, T cells follicular helper, T cells regulatory, Macrophages M0, and the lower proportion of T cells CD4 memory resting, NK cells resting, Monocytes, and Mast cells resting. Conclusion Elevated SNRPA enhances tumor cell proliferation and correlated with poor prognosis and immune infiltrates in patients with HCC.
危险品化学品经营许可证（带存储）