Role of a novel oncogene in mesothelioma

描述(申请人提供)：职业性癌症恶性间皮瘤在美国每年新诊断的人数高达3,000人，这些患者中的大多数将在确诊后12个月内死亡，无论接受何种治疗。在美国，仍有数百万人面临风险，在发展中国家，面临风险的人数预计还会攀升，因为这些国家继续使用石棉，往往没有保护措施。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的启动和维持所需的分子机制。尽管一些研究人员已经描述了间皮瘤细胞中某些基因表达的增加，但没有癌基因被证明具有功能重要性。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改变细胞，它在几乎所有间皮瘤细胞系和所研究的大多数间皮瘤肿瘤中都有高水平的消息和蛋白质表达。进一步的初步研究表明，反义CASM在体内外均能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。根据这项工作，我们形成了这样的假设：在石棉诱导的恶性间皮瘤中，CASM表达的升高在恶性表型的发生和维持中起着关键作用。为了确定CASM表达在间皮瘤细胞恶性表型中的作用，将使用正义和反义策略以及小的抑制性RNA进行一系列功能丧失和功能获得的实验。重要的功能实验也将通过开发一种转基因小鼠在体内进行，这种转基因小鼠将以组织特异性的方式有条件地表达CASM。重点将放在CASM在调节细胞周期蛋白表达中的作用。然后将进行放线菌素追逐和突变分析实验，以确定CASM是否通过破坏这些蛋白质的信息而对细胞周期产生影响。最后，实验将确定石棉是否特异性地诱导CASM的表达，以及它是通过活性氧物种还是通过其他已知的机制，如整合素黏附。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洞察力。

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.