Role of the tumor suppressor Fus1 in asbestos-induced inflammatory cancers

肿瘤抑制因子 Fus1 在石棉诱发的炎症性癌症中的作用

• 批准号: 8060611
• 负责人: Alla V Ivanova
• 金额: $ 23.13万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060611
• 关键词: 3p21.3; Acute; Affect; Agreement; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Asbestos; Autoimmune Diseases; Autoimmune Process; Biological Response Modifiers; Blood Vessels; Cancer Etiology; Cancer cell line; Cells; Chronic; Clinical; Complex; DNA Binding Domain; DNA copy number; Data; Development; Diagnosis; Disease; Down-Regulation; Epithelial; Epithelial Cell Proliferation; Event; Exposure to; Fiber; Frequencies; Future; Genes; Genomics; Glomerulonephritis; Greater sac of peritoneum; Growth; Histology; Human; Immune; Immune system; In Vitro; Indium; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interleukin-15; Kidney; Knock-out; Knockout Mice; Lead; Link; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant Pleural Mesothelioma; Malignant neoplasm of lung; Mesothelial Cell; Mesothelioma; Mesothelium; Messenger RNA; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Neoplasms in Vascular Tissue; Organism; PDAP2 Gene; Pathway interactions; Patients; Peritoneum; Phenotype; Play; Pleural; Post-Translational Protein Processing; Predisposition; Process; Property; Proteins; Reactive Oxygen Species; Recurrence; Representational Oligonucleotide Microarray Analysis; Resistance; Role; Side; Site; Specimen; Staging; Stimulus; Survival Rate; Testing; Therapeutic; Time; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Vasculitis; Xenograft procedure; base; catalase; clinically significant; cytokine; design; in vivo; insight; mouse model; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutic intervention; promoter; public health relevance; response; tool; transcription factor; tumor; tumor growth; tumor initiation; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): FUS1 is a novel tumor suppressor located in the critical 3p21.3 chromosomal region frequently deleted in multiple cancers. We recently showed that Fus1-deficient mice that we generated display a complex immuno- inflammatory phenotype with a predisposition to cancer. This proposal aims to investigate the effects of the loss of tumor suppressor Fus1 on asbestos--triggered tumor initiation and growth. Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to chronic inflammation of pleural cells caused by asbestos exposure. MPM is locally invasive and notoriously chemo-resistant tumor with the survival rate of 10-12 months from the time of diagnosis. It takes about 25-50 years for a patient to develop clinical manifestations of the disease after initial asbestos exposure. Asbestos fibers lodged in the cells of the mesothelial layer cause persistent inflammation and produce genotoxic effect on mesothelial cells. In our preliminary study, we demonstrated FUS1 insufficiency in MM through different approaches. First, FUS1 down-regulation in the majority of MM specimens (~84%) was established at the mRNA and protein levels. Second, our analysis of genomic re-arrangements by Representational Oligonucleotide Microarray Analysis (ROMA) revealed a 3p21.3 loss in ~36% of MMs including stage 1 tumors. Third, pursuing a possible link between FUS1 and exposure to asbestos, we established involvement of asbestos-generated reactive oxygen species (ROS) in FUS1 down-regulation. Finally, global profiling of FUS1 transcriptional effects in MM showed that FUS1 stimulated expression of multiple genes with tumor suppressor properties and down- regulated pro-tumorigenic genes supporting its role as a tumor suppressor. In agreement with our knockout model, FUS1 up-regulated IL-15 and also modulated expression of more than 40 other genes (~20% of total FUS1-affected genes) associated with immune system. Finally, clinical significance of FUS1 transcriptional effects was validated on the expression array data produced on 30 MM and 7 control specimens. This analysis showed that ~23% of cancer-associated FUS1 targets may contribute to MPM progression and serve in future as novel therapeutic targets. Altogether these data suggest that Fus1 plays an important anti-inflammatory and anti-tumorigenic role in MPM and underscore its importance as a transcriptional regulator of immune and anti- tumorigenic pathways. We, therefore, hypothesize that the loss of FUS1 activity alters the asbestos- induced inflammatory response in the site of asbestos lodging and contributes to the development of asbestos-induced MM. This hypothesis will be tested with three specific aims: Aim 1, will characterize the inflammatory response to asbestos in the peritoneum of Fus1-deficient mice, Aim 2, will assess susceptibility of Fus1-deficient mice to the development of asbestos-induced tumors, and Aim 3, will characterize Fus1- dependent molecular changes in the asbestos-exposed inflamed mesothelium and explore the transcriptional effect of Fus1 on the promoter of one of its target, the STRA13/bHLHB2 transcription factor. PUBLIC HEALTH RELEVANCE: We propose to use the Fus1 knockout mouse model that we have recently generated and characterized to delineate the role of the tumor suppression protein Fus1 in the organism's response to asbestos. We will explore susceptibility of these mice to asbestos-induced inflammation and mesothelioma and characterize Fus1-dependent molecular changes in asbestos-exposed tissues. We will also investigate into the molecular mechanisms of the Fus1 tumor suppressor and immune modulator activities, which will help in understanding the molecular basis of these processes and will provide new approaches for designing therapeutic tools for treatment of inflammation-caused diseases.

描述（由申请人提供）：FUS 1是一种新型肿瘤抑制因子，位于染色体关键3p21.3区域，在多种癌症中经常缺失。我们最近发现，我们产生的Fus 1缺陷小鼠显示出复杂的免疫炎症表型，具有癌症易感性。该提案旨在研究肿瘤抑制因子Fus 1的缺失对石棉引发的肿瘤发生和生长的影响。 恶性胸膜间皮瘤（MPM）是一种侵袭性肿瘤，与石棉暴露引起的胸膜细胞慢性炎症有关。MPM是一种局部侵袭性和众所周知的化疗耐药肿瘤，从诊断时起生存率为10-12个月。患者在初次接触石棉后大约需要25-50年才能出现疾病的临床表现。间皮层细胞中的天冬氨酸纤维引起持续性炎症，并对间皮细胞产生遗传毒性作用。 在我们的初步研究中，我们通过不同的方法证明了MM中的FUS 1不足。首先，在mRNA和蛋白水平上确定了大多数MM标本（约84%）中的FUS 1下调。其次，我们通过代表性寡核苷酸微阵列分析（ROMA）对基因组重排进行的分析显示，约36%的NSCLC（包括1期肿瘤）中存在3p21.3缺失。第三，追求FUS 1和石棉暴露之间的可能联系，我们建立了石棉产生的活性氧（ROS）参与FUS 1下调。最后，MM中FUS 1转录作用的总体分析表明，FUS 1刺激具有肿瘤抑制特性的多个基因的表达，并且下调支持其作为肿瘤抑制因子的促肿瘤发生基因。与我们的敲除模型一致，FUS 1上调IL-15，并且还调节与免疫系统相关的40多个其他基因（约占FUS 1影响基因总数的20%）的表达。最后，在30例MM和7例对照标本的表达阵列数据上验证了FUS 1转录效应的临床意义。该分析表明，约23%的癌症相关FUS 1靶点可能有助于MPM进展，并在未来作为新型治疗靶点。总之，这些数据表明，Fus 1在MPM中发挥重要的抗炎和抗肿瘤作用，并强调其作为免疫和抗肿瘤途径的转录调节因子的重要性。因此，我们假设FUS 1活性的丧失改变了石棉寄宿部位的石棉诱导的炎症反应，并有助于石棉诱导的MM的发展。该假设将通过三个具体目标进行测试：目的1，将描述Fus 1缺陷小鼠腹膜中对石棉的炎症反应，目的2，将评估Fus 1缺陷小鼠对石棉诱发肿瘤发展的敏感性，目标3将描述暴露于石棉的发炎间皮中Fus 1依赖性分子变化的特征，并探索Fus 1对其靶点之一的启动子的转录效应，STRA 13/bHLHB 2转录因子。 公共卫生关系：我们建议使用Fus 1基因敲除小鼠模型，我们最近产生和特点描绘的肿瘤抑制蛋白Fus 1在生物体的石棉反应的作用。我们将探讨这些小鼠对石棉诱导的炎症和间皮瘤的易感性，并描述石棉暴露组织中Fus 1依赖的分子变化。我们还将研究Fus 1肿瘤抑制剂和免疫调节剂活性的分子机制，这将有助于理解这些过程的分子基础，并将为设计治疗炎症引起的疾病的治疗工具提供新的方法。