The Role of JAB1 in osteosarcoma pathogenesis

描述（由申请人提供）：本项目的目的是了解进化保守因子JAB 1在骨肉瘤发病机制中的特定作用。癌症，特别是其致命的转移形式，造成毁灭性的生命损失和对我们的医疗保健系统的巨大负担。确定参与转移的关键因素对于更好地 癌症诊断和治疗。近年来，转录辅因子JAB 1通过影响细胞增殖、分化、存活和细胞周期进程而成为促进肿瘤发生的新角色。JAB 1在各种癌症中过度表达，包括乳腺癌和肺癌。在某些转移瘤中，JAB 1表达与抑癌基因p27和p53的表达呈负相关。重要的是，JAB还参与DNA损伤修复，JAB 1的下调使细胞对γ射线照射更加敏感，这表明JAB 1是癌症治疗的潜在靶点。然而，JAB 1的过度表达是癌症恶性的原因还是仅仅是癌症恶性的结果仍有待确定。此外，癌细胞中JAB 1的关键下游靶点和效应物大多尚未确定。JAB功能的动物模型也非常缺乏。骨肉瘤是骨细胞的原发性恶性肿瘤，是15- 19岁人群中第5位最常见的恶性肿瘤，更好地了解骨肉瘤的发病机制有助于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因素。有趣的是，JAB是p53活性的负调节剂。然而，JAB 1在骨肉瘤发病机制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，小鼠中Jab 1的缺失导致严重的骨骼发育不良，伴随着肿瘤促进因子基质金属蛋白酶（MMPs）的表达急剧下降。此外，Jab 1缺陷的原代软骨细胞表现出加速凋亡和改变细胞周期进程，这表明DNA损伤修复缺陷。基于我们的初步研究和文献，我们假设JAB 1通过抑制肿瘤抑制因子p53和p27以及增强致癌因子MMPs直接参与骨癌的发生。为了验证这一假设，我们建议在R 03的建议中，在体内和体外两个特定的目标中评估JAB 1表达改变对骨肉瘤功能的影响。目的1：探讨下调骨肉瘤细胞株JAB 1的表达是否降低其致瘤活性。目的2是确定是否增加Jab 1表达促进骨肿瘤发生在体内p53依赖的方式，使用一种新的Col 1a 1-Jab 1转基因小鼠模型。总之，这项研究将进一步了解JAB 1在骨肉瘤发展中的潜在作用，并为骨肉瘤研究产生新的突变小鼠模型。最终，基于控制JAB 1介导的肿瘤发生的新疗法将为治疗骨肉瘤和其他更普遍的肿瘤开辟一个新时代。

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.