Chromatin remodeling protein HELLS is upregulated by inactivation of the RB-E2F pathway and is nonessential for osteosarcoma tumorigenesis.
Chromatin remodeling protein HELLS is upregulated by inactivation of the RB-E2F pathway and is nonessential for osteosarcoma tumorigenesis.
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DOI：
10.18632/oncotarget.25953
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发表时间：
2018-08-24
期刊：
影响因子：
--
通讯作者：
Benavente CA
中科院分区：
文献类型：
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作者：
Wu SC;Benavente CA
骨肉瘤是儿童和青少年最常见的原发性骨恶性肿瘤。在骨肉瘤发生中涉及的各种分子机制中，RB-E2 F途径特别重要，因为几乎所有骨肉瘤病例都显示RB-E2 F途径的改变。在这项研究中，我们研究了转录因子E2 F家族成员与Rb 1缺失型骨肉瘤肿瘤恶性程度增加相关。使用基因工程小鼠骨肉瘤模型，我们发现激活剂E2 Fs，E2 F1和E2 F3的缺失，显着延迟肿瘤进展，并增加p53/Rb 1缺陷型骨肉瘤小鼠模型的总生存期。我们还研究了淋巴特异性解旋酶（HELLS）的作用，这是一种染色质重塑蛋白，被鉴定为各种癌症中RB-E2 F信号通路的关键下游效应子。在这项研究中，我们证实了RB-E2 F通路直接调节HELLS基因的表达。我们还发现，在骨肉瘤中，HELLS mRNA上调，其蛋白过表达。利用功能丧失试验研究HELLS在人骨肉瘤中的作用，我们观察到HELLS对肿瘤的增殖和迁移没有影响。此外，我们通过产生Hells条件性敲除骨肉瘤小鼠模型来研究Hells在骨肉瘤肿瘤发展中的作用，开创了Hells在发育肿瘤模型中的研究。我们发现骨肉瘤中Hells的缺失对肿瘤的发生和小鼠的总体存活没有影响。这表明，虽然HELLS可以作为肿瘤发生和RB-E2 F通路状态的生物标志物，但它不太可能作为骨肉瘤治疗的相关靶点。
Osteosarcoma is the most common primary bone malignancy in children and adolescents. Among the various molecular mechanisms implicated in osteosarcomagenesis, the RB-E2F pathway is of particular importance as virtually all cases of osteosarcoma display alterations in the RB-E2F pathway. In this study, we examined the transcription factor E2F family members that are associated with increased malignancy in Rb1-null osteosarcoma tumors. Using genetically engineered mouse models of osteosarcoma, we found that loss of activator E2Fs, E2F1 and E2F3, significantly delays tumor progression and increases the overall survival of the p53/Rb1-deficient osteosarcoma mouse model. We also studied the role of helicase, lymphoid specific (HELLS), a chromatin remodeling protein identified as a critical downstream effector of the RB-E2F signaling pathway in various cancers. In this study, we confirmed that the RB-E2F pathway directly regulates HELLS gene expression. We also found that HELLS mRNA is upregulated and its protein overexpressed in osteosarcoma. Using loss-of-function assays to study the role of HELLS in human osteosarcoma, we observed that HELLS has no effect on tumor proliferation and migration. Further, we pioneered the study of Hells in developmental tumor models by generating Hells conditional knockout osteosarcoma mouse models to examine the role of HELLS in osteosarcoma tumor development. We found that loss of Hells in osteosarcoma has no effect in tumor initiation and overall survival of mice. This suggests that while HELLS may serve as a biomarker for tumorigenesis and for RB-E2F pathway status, it is unlikely to serve as a relevant target for therapeutics in osteosarcoma.