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。它约占人类癌症的1%，占所有癌症死亡的2%。流行病学研究表明，2,3,7,8-四氯二苯并二恶英（TCDD）等多环芳烃与MM密切相关，但TCDD暴露与MM因果关系的生物学机制尚不清楚。与其他癌症相比，MM的独特特征之一是肿瘤蛋白p53 （TP53）基因的极低基因突变率。TP53编码p53肿瘤抑制因子，p53是人类基因组的守护者。基因组不稳定性（染色体易位、非整倍体和基因突变）在MM中被广泛观察到，并揭示了p53作为人类基因组守护者的功能在MM中受到损害。我们通过一类新的非编码小rna， microRNAs （miRNAs）探索了p53在MM中失活的分子机制，最近的报道表明，一些miRNAs，如miR-34，是p53肿瘤抑制网络的重要参与者。我们假设mirna负向调节MM中的人类TP53基因。我们为该项目提出了三个目标：首先，我们将通过诱变、报告基因表达和免疫印迹分析相结合的方法鉴定靶向人类TP53基因的mirna；其次，我们将通过表达谱和miRNA抑制分析来评估MM细胞系和原代MM细胞中miRNA:TP53相互作用的病理意义；第三，我们将确定二恶英是否通过上调miRNA表达来调节p53信号。一种由二恶英上调的miRNA介导的p53失活机制将为MM患者的诊断标记和治疗干预提供独特的靶点，并为二恶英暴露与MM肿瘤发生之间的生物学相互作用提供更好的理解。公共卫生相关性：TP53基因改变在多发性骨髓瘤（MM）中是罕见的晚期事件，多发性骨髓瘤是第二常见的血液恶性肿瘤，约占所有人类癌症的1%。探索野生型TP53功能失活是否存在独特的机制是至关重要的，这是MM发展过程中早期和原始的分子事件。拟开展的研究计划是验证TP53受一类新发现的小非编码rna microRNAs （miRNAs）负调控的假设，确定在TP53基因改变之前，miRNA的失调是否有助于肿瘤的发生，并确定二恶英是否通过上调miRNA表达调控p53信号。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is one of the most common hematological neoplasms. It constitutes about 1% of human cancers and 2% of all cancer deaths. Polycylic aromatic hydrocarbons such as 2,3,7,8- tetrachlorodibenzo--dioxin (TCDD) have been closely correlated to MM by epidemiologic studies, yet the biologic mechanisms of a causal relationship between TCDD exposure and MM have not been well understood. One of the unique features of MM compared to other cancers is the extremely low genetic mutation rate of the tumor protein p53 (TP53) gene. TP53 encodes the p53 tumor suppressor, guardian of the human genome. Genomic instability (chromosome translocation, aneuploidy, and gene mutation) is widely observed in MM and reveals that the function of p53 as the guardian of the human genome is compromised in MM. We explored the molecular mechanisms of p53 inactivation in MM by a new class of noncoding small RNAs, microRNAs (miRNAs) as recent reports have demonstrated that some miRNAs such as miR-34 are important players in the p53 tumor suppressor network. We hypothesize that miRNAs negatively regulate the human TP53 gene in MM. We propose three aims for this project: first, we will identify miRNAs that target the human TP53 gene by a combination of mutagenesis, reporter expression, and immunoblotting analyses; second, we will assess the pathological significance of miRNA:TP53 interactions in MM cell lines and primary MM cells by expression profiling and miRNA inhibition assays; third, we will determine whether dioxin modulates p53 signaling by upregulating miRNA expression. A novel p53 inactivation mechanism by an miRNA, that is upregulated by dioxin, will lead to unique targets for diagnostic markers and therapeutic interventions in MM patients as well as provide a better understanding of the biological interactions between dioxin exposure and MM tumorigenesis. PUBLIC HEALTH RELEVANCE: TP53 gene alterations are rare and late events in multiple myeloma (MM), the second most common hematological malignancy constituting about 1% of all human cancers. It is critical to explore whether there are unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MM development. The proposed research plan is to test the hypothesis that TP53 is negatively regulated by microRNAs (miRNAs), a class of newly discovered small noncoding RNAs, to define whether miRNA dysregulation contributes to tumorigenesis prior to TP53 gene alterations, and to determine whether dioxin modulates p53 signaling through upregulating miRNA expression.