microRNA-155 and Lymphoma

microRNA-155 和淋巴瘤

基本信息

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)是成人中最常见的淋巴恶性肿瘤;在美国, 仅在美国,每年就有30,000例新病例被诊断出来。这种肿瘤在临床和分子水平上 异质性,只有一半的患者将生存他们的疾病。microRNA(miRNA)是非蛋白质 通过与靶转录物的3 'UTR配对来控制基因表达的编码RNA。虽然miRNAs 在癌症中经常被破坏,但它们在DLBCL发病机制中的作用仍不清楚。miRNA-155(miR-155) 155)在DLBCL的侵袭性亚型中过表达。这种miRNA的致癌性质是 在E <$-miR-155转基因小鼠中证实,而其在淋巴细胞生物学中的关键作用表现为 功能动物然而,miR-155促进淋巴瘤发生的机制仍然是未知的。 未知使用全基因组方法和验证性策略,我们发现miR-155直接与细胞凋亡相关。 靶向转录因子SMAD 5,并显著削弱TGF β/BMP介导的ID 2诱导, 致癌转录因子PAX 5的关键负调节因子。此外,我们发现DLBCL细胞 经遗传修饰以过表达miR-155或SMAD 5 shRNA的品系对生长具有抗性, TGF β 1的抑制作用与p21表达的阻断有关。本报告的总体目标 我们的建议是阐明miR-155在DLBCL中的作用,并通过以下方法检验SMAD 5靶向的假设: 破坏TGF β/BMP信号传导模块的多个下游效应物是miR-155的核心, 淋巴瘤形成我们的具体目标是:1)建立miR-155,SMAD 5和miR-155之间的相互作用。 在原代人DLBCL和来自miR-155-/-小鼠的成熟B细胞中的TGF β/BMP信号, 体外和体内ID 2调节缺陷对miR-155介导的淋巴瘤发生的贡献, 3)明确SMAD 5调节p21表达的机制,并在体内建立SMAD 5的作用。 淋巴瘤中PAX 5与miR-155过表达和SMAD 5特异性敲低相关的 迄今为止未探索的miR-155和TGF β通路之间的联系是高度相关的。这些研究 可能会塑造SMAD 5在癌症中的作用,并强调癌细胞逃避癌症的新机制。 肿瘤抑制TGF β信号。完整的下游组件的特性,这些 反应应该提高我们对正常和恶性淋巴细胞生物学的理解, 治疗性操作过表达miR-155的DLBCL的新机会。

项目成果

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Ricardo C Aguiar其他文献

Ricardo C Aguiar的其他文献

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{{ truncateString('Ricardo C Aguiar', 18)}}的其他基金

Mitochondrial 2-hydroxyglutarate dehydrogenases modulate the cellular epitranscriptome
线粒体 2-羟基戊二酸脱氢酶调节细胞表观转录组
  • 批准号:
    10322194
  • 财政年份:
    2021
  • 资助金额:
    $ 29.89万
  • 项目类别:
Mitochondrial 2-hydroxyglutarate dehydrogenases modulate the cellular epitranscriptome
线粒体 2-羟基戊二酸脱氢酶调节细胞表观转录组
  • 批准号:
    10117575
  • 财政年份:
    2021
  • 资助金额:
    $ 29.89万
  • 项目类别:
Mitochondrial 2-hydroxyglutarate dehydrogenases modulate the cellular epitranscriptome
线粒体 2-羟基戊二酸脱氢酶调节细胞表观转录组
  • 批准号:
    10541234
  • 财政年份:
    2021
  • 资助金额:
    $ 29.89万
  • 项目类别:
Oxidative stress and RNA methylation
氧化应激和 RNA 甲基化
  • 批准号:
    10330584
  • 财政年份:
    2020
  • 资助金额:
    $ 29.89万
  • 项目类别:
Oxidative stress and RNA methylation
氧化应激和 RNA 甲基化
  • 批准号:
    10569629
  • 财政年份:
    2020
  • 资助金额:
    $ 29.89万
  • 项目类别:
Post-Translational Control of TET Function in Lymphoma
淋巴瘤 TET 功能的翻译后控制
  • 批准号:
    10251482
  • 财政年份:
    2013
  • 资助金额:
    $ 29.89万
  • 项目类别:
IRF8 and lymphomagenesis
IRF8 和淋巴瘤发生
  • 批准号:
    9898227
  • 财政年份:
    2013
  • 资助金额:
    $ 29.89万
  • 项目类别:
Post-Translational Control of TET Function in Lymphoma
淋巴瘤 TET 功能的翻译后控制
  • 批准号:
    10512054
  • 财政年份:
    2013
  • 资助金额:
    $ 29.89万
  • 项目类别:
Non-coding RNAs at the interface of aberrant NF-kB signals and lymphomagenesis
异常 NF-kB 信号与淋巴瘤发生界面的非编码 RNA
  • 批准号:
    8974297
  • 财政年份:
    2013
  • 资助金额:
    $ 29.89万
  • 项目类别:
IRF8 and lymphomagenesis
IRF8 和淋巴瘤发生
  • 批准号:
    9235548
  • 财政年份:
    2013
  • 资助金额:
    $ 29.89万
  • 项目类别:

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