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之间的因果关系的生物学机制尚不清楚。与其他癌症相比，MM的一个独特特征是肿瘤蛋白P53(TP53)基因的遗传突变率极低。TP53编码P53抑癌基因，是人类基因组的守护神。基因组不稳定性(染色体易位、非整倍体和基因突变)广泛存在于多发性骨髓瘤中，揭示了p53作为人类基因组守护者的功能在多发性骨髓瘤中的功能受损。我们通过一类新的非编码小RNA microRNAs(MiRNAs)来探讨MM中P53失活的分子机制，最近的报道表明，一些miRNAs如miR-34在P53抑癌网络中起着重要的作用。我们假设miRNAs在MM中负向调节人类TP53基因。我们提出了这个项目的三个目标：第一，我们将通过突变、报告表达和免疫印迹分析相结合的方法来鉴定针对人类TP53基因的miRNAs；第二，我们将通过表达谱和miRNA抑制试验来评估miRNA：TP53相互作用在MM细胞系和原代MM细胞中的病理意义；第三，我们将确定二恶英是否通过上调miRNA的表达来调节p53信号。一种新的由二恶英上调的miRNA失活P53的机制，将为MM患者的诊断标记和治疗干预提供独特的靶点，并提供更好的了解二恶英暴露和MM肿瘤发生之间的生物相互作用。

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.