The Role of JAB1 in osteosarcoma pathogenesis

JAB1在骨肉瘤发病机制中的作用

• 批准号: 8637020
• 负责人: Guang Zhou
• 金额: $ 7.69万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637020
• 关键词: 19 year old; Affect; Animal Model; Apoptosis; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cells; Chondrocytes; Common Neoplasm; Correlation Studies; DNA Repair; Defect; Development; Diagnosis; Down-Regulation; Elderly; Exhibits; Genetic; Goals; Healthcare Systems; Human; In Vitro; Individual; Lead; Life; Link; Literature; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Matrix Metalloproteinases; Mediating; Molecular; Mus; Neoplasm Metastasis; Oncogenic; Osteoblasts; Paget' s Disease; Pathogenesis; Patients; Prevention; Property; Protein p53; Research; Role; Stem cells; TP53 gene; Teenagers; Testing; Tissue Microarray; Transgenic Mice; Tumor Suppressor Proteins; Work; base; bone; bone cell; bone turnover; cancer cell; cancer diagnosis; cancer stem cell; cancer therapy; cell motility; cofactor; effective therapy; in vivo; insight; irradiation; knock-down; malignant breast neoplasm; migration; mouse model; mutant mouse model; new therapeutic target; novel; osteosarcoma; public health relevance; skeletal dysplasia; small hairpin RNA; tumor; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): The goal of this project is to understand the specific role of evolutionarily conserved factor JAB1 in osteosarcoma pathogenesis. Cancer, especially in its deadly metastatic form, causes devastating loss of life and enormous burdens on our health care system. Identifying the critical factors involved in metastasis is essential for better cancer diagnosis and treatment. In recent years, transcriptional cofactor JAB1 has emerged as a novel player of promoting tumorigenesis via its effects on cell proliferation, differentiation, survival, and cell cycle progression. JAB1 is over-expressed in various cancers, including breast and lung cancers. JAB1 expression is inversely correlated with the expression of tumor suppressor p27 and p53 in some metastases. Importantly, JAB is also involved in DNA damage repair, and the down-regulation of JAB1 rendered cells more sensitive to gamma-irradiation, indicating that JAB1 is a potential target in cancer treatment. However, it remains to be determined whether the over-expression of JAB1 is the cause or just a consequence of cancer malignancy. Furthermore, the key downstream targets and effectors of JAB1 in cancer cells remain mostly unidentified. The animal model for JAB function is also very much lacking. Osteosarcoma, the primary malignancy of bone cells, is the 5th most frequent malignancy in 15- to 19-year-olds, and a better understanding of the pathogenesis of osteosarcoma is warranted for better diagnosis and treatment of these patients. Recent mouse genetics studies demonstrated that p53 is the determining factor in the pathogenesis of osteosarcoma. Interestingly, JAB is a negative regulator of p53 activity. However, the role of JAB1 in osteosarcoma pathogenesis is largely unknown. Interestingly, our preliminary study revealed that the loss of Jab1 in mice leads to severe skeletal dysplasia, accompanied by the drastically decreased expression of tumor-promoting factors matrix metalloproteinases (MMPs). Furthermore, Jab1-deficient primary chondrocytes exhibited accelerated apoptosis and altered cell cycle progression, suggesting a DNA-damage repair defect. Based on our preliminary study and the literature, we hypothesize that JAB1 is directly involved in the tumorigenesis of bone cancer by repressing tumor suppressors p53 and p27 and enhancing oncogenic factors MMPs. To test this hypothesis, we propose to evaluate the effect of altered JAB1 expression on osteosarcoma function both in vivo and in vitro in two specific aims in this R03 proposal. Aim 1 is to determine whether down-regulating JAB1 expression in osteosarcoma cell line reduces its tumorigenic activity. Aim 2 is to determine whether increased Jab1 expression promotes bone tumorigenesis in vivo in a p53-dependent manner, using a novel Col1a1-Jab1 transgenic mouse model. Overall, this study will further our understanding of the potential role of JAB1 in osteosarcoma development and generate novel mutant mouse models for osteosarcoma research. Ultimately, new therapies based on controlling the JAB1- mediated tumorigenesis will open a new era in treating osteosarcoma and other more prevalent tumors.

项目描述（由申请人提供）：本项目旨在了解进化保守因子JAB1在骨肉瘤发病机制中的具体作用。癌症，尤其是致命的转移性癌症，给我们的医疗保健系统造成了毁灭性的生命损失和巨大的负担。确定与转移有关的关键因素对于更好的治疗至关重要