Department of General Surgery, Jiangyin People's Hospital, The Affiliated Jiangyin Clinical College of Xuzhou Medical University, Jiangyin, Jiangsu Province, China.
Department of Oncology, First People's Hospital of Yancheng, Fourth Affiliated Hospital of Nantong University, Yancheng, China.
J Cancer Res Clin Oncol. 2024 Aug 30;150(8):406. doi: 10.1007/s00432-024-05927-8.
Radiotherapy is an important strategy for the treatment of advanced gastric cancer (GC), while the radioresistance limits its effectiveness. Nucleolar and spindle associated protein 1 (NUSAP1) was implicated in cancer progression and chemoresistance. However, the underlying mechanisms of NUSAP1 influencing GC radioresistance remain largely unknown.
Meta-analysis was conducted to systematically evaluate the prognostic value of NUSAP1 in human cancers. Gene set enrichment analysis (GSEA) was conducted using The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) datasets. MRNA and protein expressions were detected by qRT-PCR and western blot, respectively. The radiosensitivity of GC cells was observed by colony formation, flow cytometry, comet, immunofluorescence, and animal assays. Immunoprecipitation assay and mass spectrometry were utilized to identify protein associations. MiRNAs binding with NUSAP1 were determined by starbase prediction, luciferase reporter, and RNA immunoprecipitation (RIP) assays.
NUSAP1 high expression predicted worse overall survival (OS) and disease-free survival (DFS) with no statistical heterogeneity through the meta-analysis. Downregulation of NUSAP1 significantly increased GC radiosensitivity by inhibiting colony formation, DNA damage repair, and promoting apoptosis following irradiation. Additionally, NUSAP1 silencing combined with radiation resulted in a synergistic anti-tumor effect in xenograft mouse model. Mechanistically, NUSAP1 interacted with ANXA2, protecting it against protein degradation via impeding its ubiquitination process. NUSAP1 was confirmed as a target of miR-129-5p and negatively regulated by it.
Our results suggested that NUSAP1 enhanced the radioresistance of GC cells. NUSAP1 could be a promising target to increase GC radiosensitivity.
放疗是治疗晚期胃癌（GC）的重要策略，但其放射抵抗限制了其疗效。核仁纺锤体相关蛋白 1（NUSAP1）参与癌症进展和化疗耐药。然而，NUSAP1 影响 GC 放射抵抗的潜在机制在很大程度上尚不清楚。
进行荟萃分析以系统评估 NUSAP1 在人类癌症中的预后价值。使用癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）数据集进行基因集富集分析（GSEA）。通过 qRT-PCR 和 Western blot 分别检测 mRNA 和蛋白质表达。通过集落形成、流式细胞术、彗星实验、免疫荧光和动物实验观察 GC 细胞的放射敏感性。利用免疫沉淀和质谱鉴定蛋白相互作用。通过 starbase 预测、荧光素酶报告和 RNA 免疫沉淀（RIP）实验确定与 NUSAP1 结合的 miRNAs。
荟萃分析显示，NUSAP1 高表达预示着总体生存（OS）和无病生存（DFS）较差，且无统计学异质性。下调 NUSAP1 可显著增加 GC 的放射敏感性，抑制集落形成、DNA 损伤修复，并促进照射后细胞凋亡。此外，NUSAP1 沉默联合放疗在异种移植小鼠模型中产生协同抗肿瘤作用。机制上，NUSAP1 与 ANXA2 相互作用，通过阻止其泛素化过程来保护其免受蛋白降解。NUSAP1 被证实是 miR-129-5p 的靶标，并受其负调控。
我们的研究结果表明，NUSAP1 增强了 GC 细胞的放射抵抗性。NUSAP1 可能是增加 GC 放射敏感性的有前途的靶点。
