The Role of JAB1 in osteosarcoma pathogenesis

描述(申请人提供)：本项目的目标是了解进化保守因子JAB1在骨肉瘤发病机制中的具体作用。癌症，特别是其致命的转移形式，会造成毁灭性的生命损失，并给我们的医疗保健系统带来巨大的负担。确定与转移有关的关键因素对于更好地 癌症诊断和治疗。近年来，转录辅助因子JAB1通过对细胞增殖、分化、存活和细胞周期进程的影响而成为促进肿瘤发生的新分子。JAB1在多种癌症中过度表达，包括乳腺癌和肺癌。在某些转移癌中，JAB1的表达与抑癌基因p27、p53的表达呈负相关。重要的是，JAB还参与DNA损伤修复，JAB1的下调使细胞对伽玛射线更加敏感，表明JAB1是癌症治疗的潜在靶点。然而，JAB1的过度表达是癌症恶性的原因还是结果仍有待确定。此外，JAB1在癌细胞中的关键下游靶点和效应物大多仍未确定。刺拳功能的动物模型也非常缺乏。骨肉瘤是一种原发于骨细胞的恶性肿瘤，在15-19岁人群中居第五位，对骨肉瘤的发病机制有更深入的了解，以便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是骨肉瘤发病的决定性因素。有趣的是，JAB是P53活性的负调节因子。然而，JAB1在骨肉瘤发病机制中的作用很大程度上是未知的。有趣的是，我们的初步研究显示，在小鼠中，Jab1基因的缺失会导致严重的骨骼发育不良，并伴随着肿瘤促进因子基质金属蛋白酶(MMPs)表达的急剧下降。此外，Jab1缺陷的原代软骨细胞表现出加速的凋亡和改变的细胞周期进程，表明DNA损伤修复缺陷。根据我们的初步研究和文献，我们推测JAB1通过抑制抑癌基因p53和p27，增强致癌因子MMPs，直接参与骨癌的发生发展。为了验证这一假说，我们建议在R03方案中评估体内和体外JAB1表达变化对骨肉瘤功能的影响。目的1是确定下调骨肉瘤细胞系中JAB1的表达是否会降低其致瘤活性。目的2利用一种新的Col1a1-Jab1转基因小鼠模型，确定Jab1表达增加是否以一种依赖于P53的方式促进体内骨肿瘤的发生。总之，这项研究将进一步加深我们对JAB1在骨肉瘤发生发展中的潜在作用的理解，并为骨肉瘤研究创造新的突变小鼠模型。最终，基于控制JAB1介导的肿瘤发生的新疗法将开启治疗骨肉瘤和其他更常见肿瘤的新纪元。

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.