Role of UHRF1 in osteosarcoma and its relationship to RB

转移仍然是骨肉瘤治疗中最重要的致死性并发症。在这些人中 发生转移的患者存活率不到五分之一。RB基因转录的基因改变 辅抑制子1(RB1)基因与增加死亡率、转移和不良反应有关 骨肉瘤的化疗。然而，发生这种情况的确切机制仍然是 已澄清。我们实验室的研究确定了uhrf1(泛素样物，含有PHD和无名指 结构域1)，作为一种在骨肉瘤中上调和蛋白过度表达的基因。Uhrf1是一个 参与表观遗传调控的多功能蛋白已被证明与Rb相互作用。此外， Rb/E2F途径直接调节uhrf1的表达。我们的数据表明，靶向uhrf1 过度表达显著提高了携带骨肉瘤小鼠的存活率，并降低了 转移的数目。这项提议的目标是确定uhrf1通过的机制(S 有助于肿瘤进展，以帮助设计新的治疗干预措施 骨肉瘤。这些研究还评估了uhrf1是否是大多数骨肉瘤的有效靶点，还是仅适用于骨肉瘤。 那些携带RB1突变的人。为此，我们将确定uhrf1在骨肉瘤发病机制中的作用。 进展，重点是它与RB1的关系，并定义每个uhrf1功能的角色 骨肉瘤中uhrf1相关迁移和侵袭的结构域。这项提议检验了这一假设 由uhrf1驱动的基因表达变化是肿瘤进展和生存不良的基础。 骨肉瘤。这项工作的顺利完成很可能直接影响到人阵1的发展。 Uhrf1对骨肉瘤和其他癌症治疗干预的相关抑制剂 过度表达。

Metastasis remains the most significant fatal complication in the treatment of osteosarcoma. Among the patients who develop metastasis, less than 1 in 5 survive. Genetic alterations at the RB transcriptional corepressor 1 (RB1) gene have been associated with increased mortality, metastasis and poor response to chemotherapy in osteosarcoma. However, the precise mechanism through which this occurs remains to be elucidated. Studies in our laboratory identified UHRF1 (Ubiquitin-like, containing PHD and RING Finger domains 1), as a gene that is upregulated and its protein overexpressed in osteosarcoma. UHRF1 is a multifunctional protein involved in epigenetic regulation that has been shown to interact with RB. Further, the RB/E2F pathway directly regulates UHRF1 expression. Our data indicates that targeting UHRF1 overexpression dramatically increases survival in mice bearing osteosarcoma tumors and reduces the rate and number of metastases. The goal of this proposal is to determine the mechanism(s) through which UHRF1 contributes to tumor progression to help design novel therapeutic interventions for the treatment of osteosarcoma. These studies also evaluate whether UHRF1 is a valid target for most osteosarcomas or only those bearing RB1 mutations. For this, we will define the role of UHRF1 in osteosarcoma pathogenesis and progression, focusing on its relationship with RB1 and define the roles of each of the UHRF1 functional domains in the UHRF1-associated migration and invasion in osteosarcoma. This proposal tests the hypothesis that gene expression alterations driven by UHRF1 underlie tumor progression and poor survival in osteosarcoma. Successful completion of this work is likely to directly influence the development of UHRF1 inhibitors relevant for therapeutic intervention for osteosarcoma and other cancers with UHRF1 overexpression.