Li Wenyue, Wang Linzhu, Tian Wen, Ji Weihang, Bing Danyang, Wang Yan, Xu Bingqian, Feng Jiayue, Zhang Peng, Liang Haihai, Gu Yunyan, Yang Baofeng
Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), State Key Laboratory of Frigid Zone Cardiovascular Diseases, College of Pharmacy, Harbin Medical University, Heilongjiang Province, China.
JCI Insight. 2024 Dec 20;9(24):e185269. doi: 10.1172/jci.insight.185269.
Osteosarcoma (OS) is the most common malignant bone tumor, characterized by a high propensity for metastasis. Recent studies have highlighted the role of alternative splicing in cancer metastasis, although the precise mechanisms underlying aberrant splicing in OS invasion and metastasis remain unclear. Here, we analyzed consistently differentially expressed genes and differentially alternative splicing events between primary and metastatic OS to identify potential genes associated with OS progression. U1 small nuclear ribonucleoprotein 70K (SNRNP70) emerged as both differentially expressed and spliced, with elevated SNRNP70 levels correlating with poor prognosis in pateints with OS. Functional experiments demonstrated that SNRNP70 overexpression enhanced the proliferation and metastasis of OS cells in vitro, while its depletion reduced these capabilities in vivo. Mechanistically, SNRNP70 directly interacted with CD55, modulating its alternative splicing and promoting tumor progression in OS. Additionally, metastatic OS samples exhibited increased infiltration of resting immune cells, and single-cell RNA sequencing revealed communication between SNRNP70-expressing osteoblastic cells and macrophages via the ADGRE5/CD55 signaling pathway. Overall, our results showed that SNRNP70 knockdown inhibited OS progression, which was associated with the splicing of CD55, indicating SNRNP70 as a promising target for OS treatment.
骨肉瘤（OS）是最常见的恶性骨肿瘤，其特点是具有较高的转移倾向。最近的研究强调了可变剪接在癌症转移中的作用，尽管骨肉瘤侵袭和转移中异常剪接的精确机制仍不清楚。在这里，我们分析了原发性和转移性骨肉瘤之间持续差异表达的基因和差异可变剪接事件，以确定与骨肉瘤进展相关的潜在基因。U1小核核糖核蛋白70K（SNRNP70）在表达和剪接上均有差异，骨肉瘤患者中SNRNP70水平升高与预后不良相关。功能实验表明，SNRNP70过表达增强了骨肉瘤细胞在体外的增殖和转移能力，而其缺失则在体内降低了这些能力。机制上，SNRNP70直接与CD55相互作用，调节其可变剪接并促进骨肉瘤的肿瘤进展。此外，转移性骨肉瘤样本中静止免疫细胞的浸润增加，单细胞RNA测序揭示了表达SNRNP70的成骨细胞与巨噬细胞之间通过ADGRE5/CD55信号通路进行的通讯。总体而言，我们的结果表明，敲低SNRNP70可抑制骨肉瘤进展，这与CD55的剪接有关，表明SNRNP70是骨肉瘤治疗的一个有前景的靶点。
