An antisense RNA-mediated regulatory program that drives cancer metastasis
反义RNA介导的驱动癌症转移的调控程序
基本信息
- 批准号:10177973
- 负责人:
- 金额:$ 42.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAdjuvant TherapyAntisense RNABindingBioinformaticsBiological AssayBiologyBreast Cancer CellBreast Cancer PatientBreast Epithelial CellsBreast cancer metastasisCell physiologyCellsCellular StressClinicalComputer ModelsDataDiseaseDissectionEnhancersEnzymesEquilibriumFutureGene ExpressionGene Expression RegulationGenetic TranscriptionGoalsGrowthHigh-Throughput Nucleotide SequencingHomeostasisLongevityMalignant NeoplasmsMeasuresMediatingMessenger RNAMetabolicMetastatic breast cancerMetastatic toMethodsMolecularNQO1 geneNamesNeoplasm MetastasisNormal CellOutcomeOxidation-ReductionOxidative StressPathologicPathway interactionsPatientsPlayPoly APolyadenylationPreparationProcessProtein IsoformsProteinsPublic HealthRNARNA BindingRNA-Binding ProteinsReactive Oxygen SpeciesRegulator GenesRegulatory PathwayRelapseResearchResistanceRoleSamplingShapesSiteStressTechnologyTestingTranscriptTransfer RNAUntranslated RNAUp-RegulationXenograft ModelXenograft procedurebasecancer cellclinically relevantdifferential expressionexperienceexperimental studyhuman diseasein vivoinsightmRNA Stabilitymalignant breast neoplasmmolecular phenotypenoveloverexpressionoxidative damageprogramspromoterrecruitresponsetherapeutic targettranscription factortranscriptome sequencingtumortumor progression
项目摘要
PROJECT SUMMARY
Post-transcriptional regulatory programs play a major role in shaping the aberrant gene expression landscape
that is a hallmark of cancer progression. We have recently demonstrated that specific classes of non-coding
RNAs, such as tRNAs (Goodarzi et al, Cell, 2016) and tRNA fragments (Goodarzi et al, Cell, 2015), play major
roles in breast cancer metastasis as post-transcriptional regulators of gene expression. However, these
regulatory RNAs are but a fraction of non-coding RNAs that are differentially expressed in highly metastatic cells.
For example, antisense RNAs are a large but often ignored class of non-coding RNAs with poorly understood
functions in the cell. We recently performed a systematic analysis of antisense RNAs expressed in a panel of
poorly and highly metastatic breast cancer cells. We observed tens of antisense RNAs that are associated with
metastatic capacity. Antisense RNAs can function as post-transcriptional regulators through their ability to form
stable duplexes with their sense counterparts. However, the underlying molecular mechanisms and their role in
gene expression regulation remains largely unknown. Here, we propose a detailed dissection of our top
candidate antisense RNA, which targets the 3' UTR of the gene NQO1 and is hence named NQO1-AS, and its
function in promoting breast cancer metastasis. We hypothesize that NQO1-AS forms a stable duplex with the
3' UTR of NQO1 which precludes the protein HNRNPC from binding. HNRNPC likely acts as a regulator of
alternative poly(A) site selection in NQO1 mRNA, shifting the equilibrium towards an isoform with a truncated 3'
UTR. We hypothesize that this truncated transcript isoform has a shorter life-span. Thus, by over-expressing
NQO1-AS, highly metastatic cells post-transcriptionally increase the expression of NQO1. Enhanced NQO1
activity enables cancer cells to withstand the oxidative stress experienced during metastasis. In this study, we
seek to perform a detailed dissection of this pathway, understand its role in metastasis, and test its clinical
relevance in patients. Importantly, the enhanced NQO1 activity in highly metastatic cells can be exploited, using
adjuvant therapies, to specifically target metastatic cells in patients with invasive breast cancer.
项目摘要
转录后调控程序在形成异常基因表达景观中起着重要作用
这是癌症发展的标志我们最近已经证明,特定类别的非编码
RNA,如tRNA(Goodarzi et al,Cell,2016)和tRNA片段(Goodarzi et al,Cell,2015),在细胞内起主要作用。
作为基因表达的转录后调节因子在乳腺癌转移中的作用。但这些
调节RNA只是在高转移性细胞中差异表达的非编码RNA的一部分。
例如,反义RNA是一类很大但经常被忽视的非编码RNA,
在细胞中发挥作用。最近,我们对一组细胞中表达的反义RNA进行了系统的分析。
低转移性和高转移性乳腺癌细胞。我们观察到数十种反义RNA,
转移能力反义RNA可以作为转录后调节因子,通过它们的形成能力,
稳定的双链体与它们的有义对应物。然而,潜在的分子机制及其在
基因表达调控在很大程度上仍是未知的。在这里,我们提出了一个详细的解剖我们的顶部
候选反义RNA,其靶向基因NQO 1的3' UTR,因此被命名为NQO 1-AS,及其
具有促进乳腺癌转移的作用。我们假设NQO 1-AS与
NQO 1的3' UTR,其阻止蛋白质HNRNPC结合。HNRNPC可能是一个监管机构,
选择NQO 1 mRNA中的poly(A)位点,使平衡向具有截短的3'端
UTR。我们推测,这种截短的转录异构体具有较短的寿命。通过过度表达,
NQO 1-AS,高转移性细胞转录后增加NQO 1的表达。增强型NQO 1
活性使癌细胞能够承受转移过程中经历的氧化应激。本研究
试图对这一通路进行详细的解剖,了解其在转移中的作用,并测试其临床意义。
患者的相关性。重要的是,在高转移性细胞中增强的NQO 1活性可以利用,
辅助治疗,以特异性靶向浸润性乳腺癌患者的转移细胞。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Hani Goodarzi其他文献
Hani Goodarzi的其他文献
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{{ truncateString('Hani Goodarzi', 18)}}的其他基金
Leveraging natural phenotypic variations of heterogenous ALS populations-in-a-dish to enable scalable drug discovery
利用培养皿中异质 ALS 群体的自然表型变异来实现可扩展的药物发现
- 批准号:
10478452 - 财政年份:2022
- 资助金额:
$ 42.59万 - 项目类别:
Leveraging natural phenotypic variations of heterogenous ALS populations-in-a-dish to enable scalable drug discovery
利用培养皿中异质 ALS 群体的自然表型变异来实现可扩展的药物发现
- 批准号:
10706307 - 财政年份:2022
- 资助金额:
$ 42.59万 - 项目类别:
Editing CG and non-CG DNA methylation to identify genomic elements that regulate gene expression
编辑 CG 和非 CG DNA 甲基化以识别调节基因表达的基因组元件
- 批准号:
10655625 - 财政年份:2021
- 资助金额:
$ 42.59万 - 项目类别:
The RNA structural code underlying pathological regulation of RNA splicing in metastasis
转移中RNA剪接病理调控的RNA结构密码
- 批准号:
10654522 - 财政年份:2021
- 资助金额:
$ 42.59万 - 项目类别:
The RNA structural code underlying pathological regulation of RNA splicing in metastasis
转移中RNA剪接病理调控的RNA结构密码
- 批准号:
10358636 - 财政年份:2021
- 资助金额:
$ 42.59万 - 项目类别:
The RNA structural code underlying pathological regulation of RNA splicing in metastasis
转移中RNA剪接病理调控的RNA结构密码
- 批准号:
10117466 - 财政年份:2021
- 资助金额:
$ 42.59万 - 项目类别:
Editing CG and non-CG DNA methylation to identify genomic elements that regulate gene expression
编辑 CG 和非 CG DNA 甲基化以识别调节基因表达的基因组元件
- 批准号:
10487529 - 财政年份:2021
- 资助金额:
$ 42.59万 - 项目类别:
An antisense RNA-mediated regulatory program that drives cancer metastasis
反义RNA介导的驱动癌症转移的调控程序
- 批准号:
10435493 - 财政年份:2019
- 资助金额:
$ 42.59万 - 项目类别:
An antisense RNA-mediated regulatory program that drives cancer metastasis
反义RNA介导的驱动癌症转移的调控程序
- 批准号:
10652579 - 财政年份:2019
- 资助金额:
$ 42.59万 - 项目类别:
Alzheimer's Administrative Supplement - An antisense RNA-mediated regulatory program that drives cancer metastasis
阿尔茨海默氏症行政补充——一种驱动癌症转移的反义 RNA 介导的调控程序
- 批准号:
10117474 - 财政年份:2019
- 资助金额:
$ 42.59万 - 项目类别:
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