文章：

Arid1a缺失促进骨肉瘤小鼠模型中的疾病进展

Arid1aLoss Enhances Disease Progression in a Murine Model of Osteosarcoma

原文发布日期：31 July 2024

DOI: 10.3390/cancers16152725

类型: Article

开放获取: 是

英文摘要：

Osteosarcoma is an aggressive bone malignancy, molecularly characterized by acquired genome complexity and frequent loss ofTP53andRB1. Obtaining a molecular understanding of the initiating mutations of osteosarcomagenesis has been challenged by the difficulty of parsing between passenger and driver mutations in genes. Here, a forward genetic screen in a genetic mouse model of osteosarcomagenesis initiated byTrp53andRb1conditional loss in pre-osteoblasts identified thatArid1aloss contributes to OS progression.Arid1ais a member of the canonical BAF (SWI/SNF) complex and a known tumor suppressor gene in other cancers. We hypothesized that the loss ofArid1aincreases the rate of tumor progression and metastasis. Phenotypic evaluation upon in vitro and in vivo deletion ofArid1avalidated this hypothesis. Gene expression and pathway analysis revealed a correlation betweenArid1aloss and genomic instability, and the subsequent dysregulation of genes involved in DNA DSB or SSB repair pathways. The most significant of these transcriptional changes was a concomitant decrease inDCLRE1C. Our findings suggest thatArid1aplays a role in genomic instability in aggressive osteosarcoma and a better understanding of this correlation can help with clinical prognoses and personalized patient care.

摘要翻译： 

骨肉瘤是一种侵袭性骨恶性肿瘤，其分子特征表现为获得性基因组复杂性及TP53与RB1基因的频繁缺失。由于难以区分基因中的乘客突变与驱动突变，获取骨肉瘤发生起始突变的分子机制认知一直面临挑战。本研究通过在成骨前体细胞中条件性敲除Trp53和Rb1基因构建的骨肉瘤发生遗传小鼠模型中进行正向遗传筛选，发现Arid1a缺失会促进骨肉瘤进展。Arid1a是经典BAF（SWI/SNF）复合物的组成成员，也是其他癌症中已知的抑癌基因。我们推测Arid1a缺失会加速肿瘤进展和转移进程。通过体外和体内Arid1a缺失的表型评估验证了这一假说。基因表达与通路分析显示，Arid1a缺失与基因组不稳定性存在相关性，并导致DNA双链断裂或单链断裂修复通路相关基因的后续失调。其中最显著的转录变化是DCLRE1C基因表达的同步下降。我们的研究结果表明，Arid1a在侵袭性骨肉瘤的基因组不稳定性中发挥作用，深入理解这种相关性将有助于临床预后判断和个体化患者管理。

原文链接：

Arid1aLoss Enhances Disease Progression in a Murine Model of Osteosarcoma