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: 7897398
• 负责人: Alla V Ivanova
• 金额: $ 19.38万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897398
• 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 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(申请人提供)：FUS1是一种新的肿瘤抑制基因，位于关键的3p21.3染色体区域，在多种癌症中经常缺失。我们最近发现，我们培育的FUS1缺陷小鼠表现出一种复杂的免疫炎症表型，并易患癌症。这项建议旨在研究肿瘤抑制基因FUS1的缺失对石棉引发的肿瘤启动和生长的影响。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，自确诊之日起存活率为10-12个月。患者在最初接触石棉后大约需要25-50年的时间才会出现这种疾病的临床表现。石棉纤维滞留在间皮层细胞中会引起持续性炎症，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实了多发性骨髓瘤的FUS1不足。首先，在大多数多发性骨髓瘤标本中(~84%)，FUS1基因在mRNA和蛋白水平上表达下调。其次，我们用代表性寡核苷酸微阵列分析(ROMA)对基因组重排的分析显示，在包括1期肿瘤在内的~36%的MMS中，3p21.3丢失。第三，探索FUS1与石棉暴露之间的可能联系，我们确定了石棉产生的活性氧(ROS)参与了FUS1的下调。最后，对多发性骨髓瘤中FUS1转录效应的全球图谱显示，FUS1刺激了多个具有肿瘤抑制特性的基因的表达，并下调了支持其作为肿瘤抑制因子的促肿瘤基因的作用。与我们的基因敲除模型一致，FUS1上调了IL-15的表达，也调节了与免疫系统相关的40多个其他基因的表达(约占FUS1影响基因总数的20%)。最后，在30个MM和7个对照样本上产生的表达阵列数据验证了FUS1转录效应的临床意义。这项分析表明，约23%的癌症相关FUS1靶点可能有助于MPM的进展，并在未来成为新的治疗靶点。总之，这些数据表明FUS1在MPM中发挥着重要的抗炎和抗肿瘤作用，并强调了它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FUS1活性的丧失改变了石棉引起的石棉倒伏部位的炎症反应，并有助于石棉诱导的MM的发展。这一假设将得到三个特定目的的验证：目的1，将表征FUS1缺陷小鼠腹膜对石棉的炎症反应，Aim 2，将评估FUS1缺陷小鼠对石棉诱导的肿瘤发生的易感性，以及Aim 3，将表征石棉暴露的炎症间皮细胞中依赖于FUS1的分子变化，并探讨FUS1对其靶标之一STRA13/bHLHB2转录因子启动子的转录影响。 公共卫生相关性：我们建议使用我们最近建立和表征的FUS1基因敲除小鼠模型来描述肿瘤抑制蛋白FUS1在生物体对石棉的反应中的作用。我们将探索这些小鼠对石棉引起的炎症和间皮瘤的敏感性，并表征石棉暴露组织中依赖FUS1的分子变化。我们还将研究FUS1抑制肿瘤和免疫调节活性的分子机制，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途径。