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.

描述（由申请人提供）：该项目的目的是了解进化保守因子JAB1在骨肉瘤发病机理中的特定作用。癌症，尤其是以致命的转移形式，会导致毁灭性的生命损失，并在我们的医疗保健系统上造成巨大负担。确定转移中涉及的关键因素对于更好 癌症诊断和治疗。近年来，转录辅助因子JAB1已成为通过对细胞增殖，分化，生存和细胞周期进程的影响促进肿瘤发生的新型参与者。 JAB1在包括乳腺癌和肺癌在内的各种癌症中过表达。 JAB1表达与某些转移酶中肿瘤抑制剂p27和p53的表达成反比。重要的是，JAB还参与了DNA损伤修复，JAB1的下调使细胞对γ-辐照更敏感，这表明JAB1是癌症治疗中的潜在靶标。但是，jab1的过度表达是癌症恶性肿瘤的原因还是尚待确定。此外，JAB1在癌细胞中的关键下游靶标和效应子仍然大部分未识别。戳戳功能的动物模型也很缺乏。骨细胞的主要恶性肿瘤是15至19岁的骨细胞的主要恶性肿瘤，对骨肉瘤的发病机理有了更好的了解，以更好地诊断和治疗这些患者。最近的小鼠遗传学研究表明，p53是骨肉瘤发病机理的决定因素。有趣的是，JAB是p53活性的负调节剂。但是，JAB1在骨肉瘤发病机理中的作用在很大程度上尚不清楚。有趣的是，我们的初步研究表明，小鼠的JAB1丧失导致严重的骨骼发育不良，并伴随着肿瘤促进因子的表达急剧降低，基质金属蛋白酶（MMPS）。此外，JAB1缺陷的原发软骨细胞表现出加速的凋亡和细胞周期进程的改变，表明DNA破坏修复缺陷。基于我们的初步研究和文献，我们假设JAB1通过抑制肿瘤抑制剂p53和p27并增强了致癌因子MMP，直接参与了骨癌的肿瘤发生。为了检验这一假设，我们建议评估JAB1表达对骨肉瘤函数的影响在体内和体外的骨肉瘤功能中的两个特定目标。 AIM 1是确定骨肉瘤细胞系中JAB1表达的下调是否会降低其肿瘤活性。 AIM 2是使用新型的Col1a1-Jab1转基因小鼠模型来确定增加的JAB1表达是否以p53依赖性方式促进了体内骨肿瘤发生。总体而言，这项研究将进一步了解JAB1在骨肉瘤开发中的潜在作用，并为骨肉瘤研究生成新型的突变小鼠模型。最终，基于控制JAB1介导的肿瘤发生的新疗法将在治疗骨肉瘤和其他更普遍的肿瘤方面开放一个新时代。