Functions of microRNAs in lymphomagenesis

描述(申请人提供)：恶性转化代表连续遗传损伤的表型终点，可导致不受控制的增殖和存活、无限的复制潜力和侵袭性生长。最近的证据表明，非编码RNA，特别是microRNAs(MiRNAs)，在肿瘤中受到基因结构和表达调控的影响。我确定了一个多顺反子miRNA簇miR17-92，作为在人类B细胞淋巴瘤中发现的染色体13q31扩增子的靶点。在B细胞淋巴瘤的小鼠模型中，增强的miR17-92表达与c-myc协同作用，通过抑制细胞死亡加速肿瘤生长。这些发现提供了一些最初的功能性证据，证明miRNAs的变化可能有助于肿瘤的发生。本申请中描述的工作继续我使用细胞培养系统和动物肿瘤模型对miR17-92致癌效应的研究。首先，我建议鉴定miR17-92簇中的致癌miRNA成分，并剖析miR17-92致癌作用的分子基础。其次，将研究miR17-92在肿瘤维持和治疗反应中的作用。最后，将结合表达研究、拷贝数研究和功能表征来更广泛地研究致癌和肿瘤抑制网络中的miRNA途径。如果这些研究成功，将对miRNAs在肿瘤发生和维持过程中的功能产生基础性的见解，可用于发现诊断标志物和治疗靶点。

DESCRIPTION (provided by applicant): Malignant transformation represents the phenotypic endpoint of successive genetic lesions that confer uncontrolled proliferation and survival, unlimited replicative potential, and invasive growth. Recent evidence has suggested that non-coding RNAs, in particular, microRNAs (miRNAs), are subjected to changes in gene structure and expression regulation in tumors. I identified a polycistronic miRNA cluster, mir17-92, as a target of chromosome 13q31 amplicon found in human B-cell lymphomas. In a mouse model for B-cell lymphoma, enforced mir17-92 expression cooperates with c-myc and accelerates tumor growth by repressing cell death. These findings provided some of the first functional evidence that changes in miRNAs could contribute to oncogenesis. The work described in this application continues my studies on the oncogenic effects of mir17-92 using both cell culture systems and animal tumor models. First, I propose to identify the oncogenic miRNA components within the mir17-92 cluster, and to dissect the molecular basis for the tumorigenic effects of mir17-92. Second, the effects of mir17-92 in tumor maintenance and therapy response will be investigated. Finally, combined expression studies, copy number studies and functional characterization will be applied to examine more broadly the miRNA pathways in the oncogenic and tumor suppressor network. These studies, if successful, will produce fundamental insights into the functions of miRNAs during tumor development and tumor maintenance, which can be applied for discovery of both diagnostic markers and therapeutic targets.