NUSAP1调节类风湿性关节炎成纤维细胞样滑膜细胞表型，涉及关节损伤、糖酵解和癌症相关的转录组特征

IF 0.9 Q4 GENETICS & HEREDITY

Gene Reports Pub Date : 2025-05-25 DOI:10.1016/j.genrep.2025.102270

Teresina Laragione , Carolyn Harris , Aurelien Pélessier , Percio S. Gulko

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引用次数: 0

摘要

成纤维细胞样滑膜细胞（FLS）在类风湿关节炎（RA）发病过程中起核心作用，其侵袭行为与疾病严重程度和关节损伤密切相关。然而，对FLS侵袭性的调控尚不完全清楚。核仁和纺锤体相关蛋白1 （NUSAP1）基因与癌细胞的侵袭和预后有关，我们认为它也可能参与了FLS侵袭的调控。方法用siRNA敲低RA FLS中的NUSAP1，并与对照siRNA进行比较。然后研究细胞的侵袭、迁移、增殖和粘附实验，并使用RNA进行RNA测序以及途径和共表达网络分析。结果NUSAP1的sirna敲低显著降低了RA FLS的侵袭性（P = 0.002）和在划痕/创面愈合试验中的迁移（P = 0.024）。RNA测序分析显示，NUSAP1敲低显著影响不同类型癌症和癌症生物学的过程，包括细胞周期、DNA复制、转录、RHO GTPase信号传导、细胞分裂和细胞代谢途径的调节，包括糖酵解。NUSAP1敲除FLS中表达最显著降低的基因包括ARHGAP11A、ANLN、PRC1和RACGAP1，以及先前与癌症侵袭和迁移有关的4个基因，以及包括KIF1c在内的18个已知调节FLS侵袭的激酶家族基因。结论我们描述了NUSAP1在RA FLS侵袭、迁移和糖酵解调控中的新作用，这些都与疾病的发病机制和关节损伤有关，并鉴定了该基因调控的一个新的转录组特征。这些发现提高了NUSAP1或其靶基因和途径之一可能成为RA新治疗的新预后标记物或靶标的可能性。

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NUSAP1 regulates rheumatoid arthritis fibroblast-like synoviocyte phenotypes implicated in joint damage, glycolysis, and a cancer-associated transcriptomic signature

Background

The fibroblast-like synoviocyte (FLS) has a central role in rheumatoid arthritis (RA) pathogenesis and its invasive behavior strongly correlates with disease severity and joint damage. Yet, the regulation of FLS invasiveness has been incompletely characterized. The nucleolar and spindle associated protein 1 (NUSAP1) gene has been implicated in cancer cell invasion and outcomes, and we considered that it might also be involved in the regulation of FLS invasiveness.

Methods

siRNA was used to knockdown NUSAP1 in RA FLS, compared with a control siRNA. Cells were then studied in invasion, migration, proliferation and adhesion assays, and RNA was used for RNA sequencing and for both pathway and co-expression network analyses.

Results

siRNA knockdown of NUSAP1 significantly reduced RA FLS invasiveness (P = 0.002) and migration in the scratch/wound healing assay (P = 0.024). RNA sequencing analyses revealed that NUSAP1 knockdown significantly affected processes implicated in different types of cancer and in cancer biology, including cell cycle, DNA replication, transcription, RHO GTPase signaling, regulation of cytokinesis and cell metabolism pathways, including glycolysis. Among the genes with the most significantly decreased expression in FLS knocked down for NUSAP1 were ARHGAP11A, ANLN, PRC1 and RACGAP1, four genes previously implicated in cancer invasion and migration, and eighteen kinesin family genes, including KIF1c, known to regulate FLS invasion.

Conclusion

We describe a new role for NUSAP1 in the regulation of the RA FLS invasiveness, migration, and glycolysis, all relevant to disease pathogenesis and joint damage, and identify a new transcriptomic signature regulated by this gene. These findings raise the possibility that NUSAP1, or one of its target genes and pathways may become a new prognostic marker or target for new therapies for RA.

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.