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Role of UHRF1 in osteosarcoma and its relationship to RB

UHRF1在骨肉瘤中的作用及其与RB的关系

基本信息

批准号：
10759010
负责人：
Claudia Andrea Benavente
金额：
$ 12.17万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10759010
关键词：
Biology Cell Cycle Regulation Cell Line Cells Childhood Solid Neoplasm Clinical Complication DNA Methylation Data Development Epigenetic Process Family Gene Expression Alteration Genes Genetic Transcription Goals Health Histone Acetylation Human In Vitro Incidence Invaded Knock-out Knockout Mice Laboratories Link Malignant Neoplasms Mediating Metastatic Neoplasm to the Lung Mus Mutation Neoplasm Metastasis PHD Finger Pathogenesis Pathway interactions Patients Phenotype Play Primary Bone Osteosarcoma Prognosis Promoter Regions Proteins Research Research Proposals Ring Finger Domain Role Site Structure of parenchyma of lung TP53 gene Testing Therapeutic Therapeutic Intervention Ubiquitin Ubiquitination Work anticancer treatment cancer therapy cell motility chemotherapy design effective therapy epigenetic regulation epigenome gain of function genetic corepressor histone methylation improved in vivo inhibitor inhibitor therapy knock-down loss of function migration mortality mouse model next generation novel novel therapeutic intervention osteosarcoma overexpression preservation recruit response therapeutic target tumor tumor progression tumorigenesis tumorigenic virtual

项目摘要

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.

转移仍然是骨肉瘤治疗中最重要的致命并发症。在