microRNA-155 and Lymphoma

microRNA-155 和淋巴瘤

基本信息

批准号：
8403658
负责人：
Ricardo C Aguiar
金额：
$ 28.1万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403658
关键词：
3&apos Untranslated Regions Address Adult Animals B-Lymphocytes Behavior Binding Biological Assay Biological Models Biology Birds Cell Line Cells Classification Code Collection Data Development Diagnosis Disease Epithelial Cells Gene Expression Genes Goals Growth Human Immune System Diseases In Vitro Knockout Mice Link Lymphocyte Biology Lymphoma Lymphomagenesis Malignant - descriptor Malignant Neoplasms Malignant lymphoid neoplasm Mature B-Lymphocyte Mediating Messenger RNA MicroRNAs Modeling Molecular Mus Nature Oncogenic PAX5 gene Pathogenesis Pathway interactions Patients RNA Regulation Regulator Genes Reporter Reporting Research Proposals Resistance Role Signal Transduction Site TCF3 gene Testing Therapeutic Transcript Transforming Growth Factors Transgenic Mice Translations Tumor Escape Tumor Suppressor Proteins United States Viral Xenograft Model bone morphogenic protein cancer cell cohort cytokine forging genome-wide grasp human ID2 protein improved in vivo insight large cell Diffuse non-Hodgkin&apos s lymphoma loss of function malignant lymphocyte neoplastic cell novel overexpression response small hairpin RNA therapeutic development therapeutic target transcription factor tumor

项目摘要

Diffuse Large B-cell Lymphoma (DLBCL) is the most common lymphoid malignancy in adults; in the United States alone 30.000 new cases are diagnosed every year. This tumor is clinically and molecularly heterogeneous and only half of the patients will survive their disease. MicroRNAs (miRNA) are non-protein coding RNAs which control gene expression by pairing to the 3'UTR of target transcripts. Although miRNAs are often disrupted in cancer, their role in the pathogenesis of DLBCL remains unclear. MiRNA-155 (miR- 155) is overexpressed in aggressive subtypes of DLBCL. The oncogenic nature of this miRNA was confirmed in E¿-miR-155 transgenic mice, whereas its key role in lymphocyte biology was shown in loss of function animals. However, the mechanisms by which miR-155 contributes to lymphomagenesis are still unknown. Using genome-wide approaches and confirmatory strategies we uncovered that miR-155 directly targets the transcription factor SMAD5 and significantly impairs the TGF¿/BMP-mediated induction of ID2, a key negative regulator of the oncogeneic transcription factor PAX5. Furthermore, we found that DLBCL cell lines genetically modified to overexpress miR-155 or a SMAD5 shRNA become resistance to the growth inhibitory effects of TGF¿1 in association with a block in p21 expression. The overall objective of this proposal is to elucidate the role of miR-155 in DLBCL and test the hypothesis that SMAD5 targeting, by disrupting multiple downstream effectors of the TGF¿/BMP signaling module, is at the core of the miR-155 lymphomagenesis. Our specific aims are: 1) Establish the interplay between miR-155, SMAD5 and TGF¿/BMP signals in primary human DLBCLs and mature B-cells from miR-155-/- mice, 2) Characterize in vitro and in vivo the contribution of a defective ID2 regulation to miR-155-mediated lymphomagenesis and, 3) Define the mechanisms by which SMAD5 regulates p21 expression, and establish in vivo the role of PAX5 in the lymphomas associated with miR-155 overexpression and SMAD5-specific knockdown. The hitherto unexplored connection between miR-155 and the TGF¿ pathway is highly relevant. These studies could forge a role for SMAD5 in cancer and highlight a novel mechanism by which cancer cells escape the tumor suppressing TGF¿ signals. Complete characterization of the downstream components of these responses should improve our understanding of normal and malignant lymphocyte biology and uncover novel opportunities for therapeutic manipulation of DLBCLs overexpressing miR-155.

弥漫性大B细胞淋巴瘤（DLBCL）是成年人中最常见的淋巴性恶性肿瘤。在曼联每年仅诊断出30.000例新病例。该肿瘤在临床上和分子上是异质性和只有一半的患者能够在其疾病中生存。 microRNA（miRNA）是非蛋白编码RNA，通过将基因表达与目标转录的3'UTR配对控制基因表达。虽然mirnas 通常在癌症中被破坏，它们在DLBCL发病机理中的作用尚不清楚。 miRNA-155（mir- 155）以DLBCL的侵略性亚型过表达。该miRNA的致癌性是在e -MIR -155中证实的转基因小鼠，而其在淋巴细胞生物学中的关键作用在丧失中显示功能动物。但是，miR-155促进淋巴细胞增多的机制仍然是未知。使用全基因组方法和确认策略，我们发现miR-155直接靶向转录因子SMAD5，并显着损害TGF。 /BMP介导的ID2的诱导癌性转录因子PAX5的关键负调节剂。此外，我们发现DLBCL细胞通常修改为过表达miR-155或smad5 shRNA的线变成了对生长的抗性 TGF¿1与P21表达中的块相关的抑制作用。总体目标建议是阐明miR-155在DLBCL中的作用，并检验以下假设：Smad5靶向。破坏TGF¿ /BMP信号模块的多个下游效应，是miR-155的核心淋巴作用。我们的具体目的是：1）建立mir-155，smad5和 TGF¿ /BMP信号中的原代人DLBCL和miR-155 - / - 小鼠的成熟B细胞，2）在体外和体内ID2调节对miR-155介导的淋巴作用的贡献以及 3）定义SMAD5调节p21表达的机制，并在体内确定作用与miR-155过表达和Smad5特异性敲低有关的淋巴瘤中的PAX5。这迄今为止，miR-155与TGF¿途径之间的意外连接非常相关。这些研究可以在癌症中扮演SMAD5的作用，并突出一种新的机制，癌细胞逃脱了抑制TGF¿信号的肿瘤。这些下游组成部分的完整表征反应应提高我们对正常和恶性淋巴细胞生物学的理解，并发现 DLBCL过表达miR-155的DLBCL热操纵的新机会。