A novel oncogene in mesothelioma

描述（由申请人提供）：在美国，每年有多达3000人新诊断为职业性恶性间皮瘤，这些患者中的大多数将在诊断后12个月内死亡，无论治疗如何。在美国，仍有数百万人处于危险之中，而在发展中国家，这一数字预计还会攀升，因为这些国家仍在使用石棉，而且往往没有任何保护措施。为了显著影响这种疾病，需要更多地了解间皮细胞恶性状态启动和维持所需的分子机制。尽管许多研究人员描述了间皮瘤细胞中某些基因表达的增加，但没有任何致癌基因被证明具有重要的功能。这项工作的初步研究表明，一种名为CaSm的独特癌基因，可能通过其在RNA信息不稳定中的作用来转化细胞，在几乎所有间皮瘤细胞系和大多数间皮瘤肿瘤中具有高水平的信息和蛋白质表达。进一步的初步研究表明，反义CaSm在体外和体内抑制间皮瘤细胞的生长。反义CaSm抑制生长与细胞特异性细胞周期改变和特定细胞周期相关蛋白表达增加有关。从这项工作中，我们形成了这样的假设：CaSm表达的升高在石棉诱导的恶性间皮瘤细胞的恶性表型的发展和维持中起着至关重要的作用，为了确定CaSm表达在间皮瘤细胞恶性表型中的作用，我们将使用正、反义策略以及小抑制rna进行一系列功能丧失和功能获得的实验。通过开发一种能够以组织特异性方式有条件表达CaSm的转基因小鼠，也将在体内进行重要的功能实验。重点将放在CaSm在调节细胞周期蛋白表达中的作用。然后进行放线菌素追踪和突变分析实验，以确定CaSm是否通过这些蛋白质的不稳定信息对细胞周期产生影响。最后，实验将确定石棉是否特异性诱导CaSm的表达，以及它是否通过活性氧或其他已知机制（如整合素粘附）诱导CaSm表达。我们相信这些研究将为这种癌症提供令人兴奋的信息和重要的见解。

DESCRIPTION (provided by applicant): The occupational cancer malignant mesothelioma is newly diagnosed in up to 3,000 persons per year in the US and most of these patients will die within 12 months of diagnosis regardless of treatment. Millions remain at risk in the US and the number at risk is expected to climb in developing nations where asbestos continues to be used, often without protection. In order to significantly impact this disease more needs to be known about the molecular mechanisms required for the initiation and maintenance of the malignant state in the mesothelial cell. Although a number of investigators have described increases in expression of some genes in mesothelioma cells, no oncogenes have been shown to have functional importance. Studies preliminary to this work show that a unique oncogene named CaSm, which is likely to transform cells through its role in RNA message destabilization, has high levels of expression of message and protein in virtually all mesothelioma cell lines and the majority of mesothelioma tumors examined. Further preliminary studies show that antisense CaSm inhibits growth of mesothelioma cells in vitro and in vivo. Antisense CaSm inhibition of growth is associated with cell-specific cell cycle alterations and increased expression of specific cell cycle-associated proteins. From this work we formed the hypothesis that: elevated CaSm expression plays a critical role in the development and maintenance of the malignant phenotype in asbestos-induced malignant mesothelioma To establish the role of CaSm expression in the malignant phenotype of mesothelioma cells, a series of loss of function and gain of function experiments will be performed using sense and antisense strategies, as well as small inhibitory RNAs. Important gain of function experiments will also be performed in vivo through the development of a transgenic mouse which will conditionally express CaSm in a tissue-specific manner. Focus will be placed upon the role of CaSm in regulation of expression of cell cycle proteins. Actinomycin chase and mutation analysis experiments will then be performed to determine if CaSm exerts its effect on cell cycle by destabilizing messages for these proteins. Finally experiments will determine whether asbestos specifically induces the expression of CaSm, and if it does so via reactive oxygen species or via other known mechanisms such as integrin adhesion. We believe these studies will provide exciting information and important insight into this cancer.