CREB-TARGET GENES IN MALIGNANT MESOTHELIOMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 恶性间皮瘤(MMS)是一种来源于胸膜和腹膜腔表面浆膜细胞的侵袭性肿瘤。MM与石棉接触有关，然而，对导致MM发生和耐药的关键细胞机制知之甚少。cAMP反应元件结合蛋白(CREB)是一种转录因子，调节多种细胞功能。CREB依赖的基因表达还与多种功能有关，如生长/存活、迁移/侵袭、血管生成和耐药性。CREB在一些癌症中的作用已经被研究，但它在多发性骨髓瘤中的作用完全不清楚。我们实验室的数据显示，石棉暴露后人间皮细胞CREB和CREB调节基因的激活增加，5个人MM系和3个MM患者的组织阵列中CREB的内源性激活也增加。我们假设CREB的激活导致参与MM各种肿瘤发生和耐药过程的CREB调控基因的表达。在本方案中，我们通过微阵列分析(U133A2 Affymetrix芯片和GeneSifter程序分析数据)研究了两种不同的MM细胞系(HMeso和PPMMill)以shCREB或阴性对照转染后共同的CREB调控基因。这项研究揭示了一组CREB调控的基因参与间皮瘤细胞系的各种致瘤过程(167个增加，279个减少2倍以上)和PPMMill(1555个增加，2144个减少2倍以上)间皮瘤细胞系。两个MM细胞系中已识别的基因的功能相关性将在一项更大的研究中得到验证和探索。识别的基因可能作为MM治疗的潜在靶点，无论是单独治疗还是与化疗药物联合治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Malignant mesotheliomas (MMs) are aggressive neoplasms that are derived from the surface serosal cells of the pleural and peritoneal cavities. MM is associated with asbestos exposure however, little is known about the crucial cellular mechanisms contributing to the development and chemoresistance of MM. cAMP response element binding protein (CREB) is a transcription factor that rgulates a variety of cellular functions. CREB-dependent gene expression is also linked to various functions like growth/survival, migration/invasion, angiogenesis and drug resistance. The role of CREB has been studied in a few cancers but its role in MM is completely unknown. Data from our laboratory show increased activation of CREB and CREB-regulated genes in human mesothelial cells after asbestos exposure as well increased endogenous activation of CREB in 5 human MM lines and in tissue arrays from 3 MM patients. We hypothesized that CREB activation leads to expression of CREB-regulated genes involved in various tumorigenesis and drug resistance process of MM. In the present proposal we studied by microarray analysis (U133A2 Affymetrix chip and GeneSifter program to analyze data) common CREB-regulated genes after transfecting two different MM cell lines (Hmeso and PPMMill) with sh CREB or negative control. This study revealed a set of CREB-regulated genes involved in various tumorigenec processes in Hmeso (167 increased and 279 decreased more than 2 fold) and PPMMill (1555 increased and 2144 decreased more than 2 fold) mesothelioma cell lines. Functional relevance of identified genes in two MM cell lines will be validated and explored in a larger study. Identified genes could possibly act as potential target for MM treatment either alone or in combination with chemotherapeutic drugs.