SNRPB 通过 RRM2 激活 ATM 信号通路,促进骨肉瘤的发展。

IF 4.7 2区 医学 Q1 PATHOLOGY American Journal of Pathology Pub Date : 2024-08-03 DOI:10.1016/j.ajpath.2024.06.015
Yongxiang Shi , Zhan Wang , Jiahao Zhang , Peiwen He , Minglei Yang , Chenglong Zhao , Bo Li , Ming Qian
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摘要

骨肉瘤是一种恶性骨肿瘤,具有高转移性和治疗后复发率的特点。据报道,作为剪接体核心成分的小核核糖核蛋白多肽 B 和 B1(SNRPB)在多种癌症类型中表现出上调。然而,SNRPB在骨肉瘤进展中的确切作用仍未得到充分阐明。在此,我们通过免疫组化染色法(IHC)检测了SNRPB在人类骨肉瘤组织和正常骨组织中的表达,结果发现SNRPB在骨肉瘤中显著上调,与存活率降低相关。此外,体外功能缺失实验表明,敲除 SNRPB 能显著抑制骨肉瘤细胞的增殖和迁移,以及 HUVECs 小管的形成,同时增强骨肉瘤细胞的凋亡。从机理上讲,我们发现SNRPB通过E2F转录因子1(E2F1)促进核糖核苷酸还原酶亚基M2(RRM2)的转录。进一步的拯救实验表明,RRM2是SNRPB诱导骨肉瘤恶性行为的必要条件。此外,我们还证实 SNRPB 在骨肉瘤细胞生长和凋亡中的功能与 ATM 信号通路的激活有关。总之,我们的研究结果初步揭示了SNRPB诱导骨肉瘤发展的内在机制,并提出将SNRPB作为骨肉瘤治疗的新靶点。
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Small Nuclear Ribonucleoprotein Polypeptides B and B1 Promote Osteosarcoma Progression via Activating the Ataxia-Telangiectasia Mutated Signaling Pathway through Ribonucleotide Reductase Subunit M2
Osteosarcoma is a malignant bone tumor characterized by high metastatic potential and recurrence rates after therapy. The small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB), core components of a spliceosome, exhibit up-regulation across several cancer types. However, the precise role of SNRPB in osteosarcoma progression remains poorly elucidated. Herein, SNRPB expression was explored in human osteosarcoma tissues and normal bone tissues by immunohistochemical staining, revealing a notable up-regulation of SNRPB in osteosarcoma, correlating with diminished survival rates. The in vitro loss-of-function experiments showed that SNRPB knockdown significantly suppressed the osteosarcoma cell proliferation and migration, as well as tubule formation of human umbilical vascular endothelial cells, while enhancing osteosarcoma cell apoptosis. Mechanistically, SNRPB promoted the transcription of ribonucleotide reductase subunit M2 via E2F transcription factor 1. Further rescue experiments indicated that ribonucleotide reductase subunit M2 was required for SNRPB-induced malignant behaviors in osteosarcoma. Additionally, the function of SNRPB in osteosarcoma cell growth and apoptosis was confirmed to be associated with ataxia-telangiectasia mutated (ATM) signaling pathway activation. In conclusion, these findings provide initial insights into the underlying mechanisms governing SNRPB-induced osteosarcoma progression, and we propose SNRPB as a novel therapeutic target in osteosarcoma management.
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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