Convergence of MicroRNAs and p53 Signaling in Multiple Myeloma: Environmental Co

描述(申请人提供)：多发性骨髓瘤(MM)是最常见的血液肿瘤之一，约占人类所有癌症的1%，占所有癌症死亡的2%。多发性肌萎缩侧索硬化症(MM)之前患有意义不明的单克隆性伽马病(MGUS)，这是一种最常见的癌前疾病，困扰着美国3%的50岁以上人口。虽然MM被认为是一种环境疾病，但目前尚不清楚是什么促进了MGUS向致命性MM的进展。MM的独特特征之一是抑癌基因P53的突变率极低。基因组不稳定性(染色体易位、非整倍体和基因突变)在多发性骨髓瘤中被广泛观察到，这表明作为人类基因组守护者的P53的功能受到了损害。我们以前通过一类新的非编码小RNA microRNAs(MiRNAs)分析了MM细胞中P53失活的分子机制。我们实验室和其他实验室的数据表明，多个miRNAs抑制人类p53基因的表达，其中大多数miRNAs在MM中过表达。我们假设普遍存在的环境污染物苯并[a]芘(BaP)和四氯二苯并二恶英(TCDD)在MM过程中破坏miRNA：p53的功能相互作用以介导p53失活。在这一新的应用中，我们提出了3个特定的目标，以促进我们对MM的分子病因的研究，并寻找潜在的治疗和预防策略。在目标1中，我们将剖析暴露于BaP和TCDD的MM细胞miRNAs上调的潜在机制。在目标2中，我们将使用小鼠同基因异种移植和遗传模型来确定BaP是否通过靶向p53的一个miRNA基因簇直接促进MM的进展。在目标3中，我们将确定表没食子儿茶素没食子酸酯(EGCG，植物药物Polyhenon(R)E的主要成分)是否可以预防或抑制由BaP或TCDD诱导的MM进展。完成本提案中的目标将揭示环境碳氢化合物在p53：miRNA相互作用和MM病因学中的作用，并为MM的预防和治疗干预提供一种重新定位的药物。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is one of the most common hematological neoplasms, constituting about 1% of all human cancers and 2% of all cancer deaths. MM is preceded by monoclonal gammopathy of undetermined significance (MGUS), one of the most common pre-cancerous conditions afflicting 3% of the United States population over 50 years old. Although MM is regarded as an environmental disease, it is not yet clear what promotes the progression from MGUS to the deadly MM. One of the unique features of MM is the extremely low mutation rate of the tumor suppressor p53 gene. Genomic instability (chromosome translocation, aneuploidy, and gene mutation) is widely observed in MM cases, suggesting that the function of p53 as the guardian of the human genome is compromised. We previously analyzed the molecular mechanisms of p53 inactivation in MM cells by a new class of noncoding small RNAs, microRNAs (miRNAs). Data from our laboratory and others have shown that multiple miRNAs suppress expression of the human p53 gene and that a majority of these miRNAs are overexpressed in MM. We hypothesize that the ubiquitous environmental pollutants benzo[a]pyrene (BaP) and tetrachlorodibenzodioxin (TCDD) disrupt functional interactions of miRNA:p53 to mediate p53 inactivation over the course of MM. In this renewal application, we propose 3 specific aims to advance our investigations into the molecular etiology of MM and identify potential treatment and preventive strategies. In Aim 1, we will dissect the underlying mechanisms of upregulation of miRNAs in MM cells exposed to BaP and TCDD. In Aim 2, we will determine, using murine syngeneic xenograft and genetic models, whether BaP directly promotes MM progression via one miRNA gene cluster that targets p53. In Aim 3, we will determine whether epigallocatechin gallate (EGCG, the main component in the botanical drug Polyphenon(R) E) prevents or inhibits MM progression induced by BaP or TCDD. Completion of the goals in this proposal will reveal the role of environmental hydrocarbons in p53:miRNA interaction and in MM etiology and provide a repurposed drug for MM prevention and therapeutic intervention.