MEG3 deletion drives lung tumorigenesis due to environmental nickel exposure
由于环境镍暴露,MEG3 缺失导致肺部肿瘤发生
基本信息
- 批准号:9852426
- 负责人:
- 金额:$ 27.75万
- 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:2019-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAutomobile DrivingBiologicalBiological AssayCRISPR/Cas technologyCancer PatientCarcinogensCell Culture TechniquesCellsClinicalDevelopmentDown-RegulationEpigenetic ProcessEpithelial CellsEventExposure toGene Expression RegulationGenesGoalsHumanIn VitroIndividualInhalationInternational Agency for Research on CancerKnock-outKnockout MiceKnowledgeLaboratory StudyLungLung NeoplasmsMalignant - descriptorMalignant neoplasm of lungMediatingMediator of activation proteinModelingMolecularMusNickelNude MiceOncogenesOncogenicOutcomeOxidative StressPlayPollutionPrevention therapyPrognostic MarkerReportingResearchRoleSignal PathwaySignal TransductionStructure of parenchyma of lungSystemTestingTimeTissuesTransducersTumor Suppressor GenesTumorigenicityUntranslated RNAUp-RegulationXenobioticsattenuationbasebronchial epitheliumc-myc Genescarcinogenicitycell transformationdeep sequencingdesignepidemiology studyexperimental studygain of functionimprovedin vivoinsightknock-downloss of functionlung carcinogenesislung tumorigenesismouse modelnew therapeutic targetnoveloverexpressionprofessional atmospheresmall hairpin RNAtherapeutic target
项目摘要
Abstract
Decades of both epidemiological research and in vitro and in vivo laboratory studies have consistently
reported an association between environmental nickel exposure and lung cancer. As early as 1990, the
International Agency for Research on Cancer (IARC) classified nickel compounds as Group 1 carcinogens:
substances confirmed as carcinogenic to humans. Although the multiple mechanisms, including oxidative
stress, epigenetic effects, and activation of signaling pathways that trigger differential gene regulation has
been thought to be associated with nickel carcinogenic effect, there is no evidence that a single nickel-
inducible factor can drive transformation of human bronchial cells, to the best of our knowledge. In our
Preliminary Studies, we performed long noncoding RNA (lncRNA) deep sequencing using the Illumina
HiSeqTM2000/2500 high throughout system to evaluate whether nickel affects the abundance of 5,929
known lncRNAs. Nickel treatment altered the levels of 24 of these lncRNAs in normal primary human
bronchial epithelial cells (HBECs), while 16 of them were verified in Real-time PCR assay. With
overexpression and/or knockdown analyses of the 16 lncRNAs, we further discovered that a reduced
abundance of maternally-expressed gene 3 (MEG3) was sufficient for malignant transformation of HBECs.
Our demonstration that MEG3 inhibition can independently transform HBECs provides the basis of our
central hypothesis that MEG3 downregulation drives transformation and tumorigenecity of HBECs after
nickel exposure. Here we propose to elucidate the molecular mechanisms that underlie our novel findings
that MEG3 downregulation is a crucial driver for nickel-induced malignant transformation of HBECs with the
following Specific Aims: 1, To test the hypothesis that p62 and C-Myc define an important MEG3-regulated
axis that promotes transformation of HBECs upon MEG3 deficiency; 2, To test the hypothesis that the
crosstalk between a p62/C-Myc cascade and the PHLPP/HIF-1α axis causes the MEG3-deficiency-
correlated malignant transformation of HBECs; 3, To explore the biological significance of MEG3 deletion
and its activated downstream molecules in lung tumoriginecity. Our novel Preliminary Findings suggest that
MEG3 is downregulated by nickel exposure both in vitro and in vivo, that knockdown of MEG3 alone can
transform HBECs, and that crosstalk between the putative signaling transducers downstream of MEG3
mediate the malignant transformation of HBECs caused by MEG3 deficiency. This proposal's strengths are
the complementary use of cell culture models and novel conditional MEG3 knockout mouse models to
examine integration of the molecular events that account for nickel-mediated lung carcinogenesis.
Clarifying these issues will provide valuable insights regarding MEG3 as a prognostic biomarker and/or as
a therapeutic target. Ultimately, both uses could improve clinical outcomes in lung cancer patients.
摘要
几十年的流行病学研究以及体外和体内实验室研究始终表明,
报告了环境镍暴露与肺癌之间的联系。早在1990年,
国际癌症研究机构(IARC)将镍化合物列为第1组致癌物:
被证实对人类致癌的物质。虽然多种机制,包括氧化
应激、表观遗传效应和触发差异基因调节的信号通路的激活,
一直被认为与镍的致癌作用有关,没有证据表明单一的镍-
据我们所知,诱导因子可以驱动人支气管细胞的转化。在我们
初步研究,我们使用Illumina进行了长非编码RNA(lncRNA)深度测序,
HiSeqTM 2000/2500高通量系统评估镍是否影响5,929丰度
已知的lncRNA镍处理改变了正常人中24种lncRNA的水平
支气管上皮细胞(HBECs),其中16个经Real-time PCR验证。与
通过对16种lncRNA的过表达和/或敲低分析,我们进一步发现,
母亲表达的基因3(MEG3)的丰度足以使HBEC恶性转化。
我们证明MEG3抑制可以独立地转化HBEC,这为我们的研究提供了基础。
中心假设MEG3下调驱动HBEC的转化和致瘤性,
镍暴露。在这里,我们建议阐明我们的新发现的分子机制
MEG3下调是镍诱导的HBEC恶性转化的关键驱动因素,
以下具体目的:1、验证p62和C-Myc定义重要的MEG3调节的细胞凋亡的假设。
2.为了验证MEG3缺乏时促进HBEC转化的轴的假设,
p62/C-Myc级联和PHLPP/HIF-1 α轴之间的串扰导致MEG3缺陷-
探讨MEG3基因缺失的生物学意义
及其激活的下游分子在肺肿瘤发生中的作用。我们新的初步发现表明,
MEG3在体外和体内都受到镍暴露的下调,单独敲低MEG3可以
转化HBEC和MEG3下游推定信号转导子之间的串扰
介导由MEG3缺陷引起的HBEC恶性转化。该提案的优势在于
补充使用细胞培养模型和新的条件性MEG3敲除小鼠模型,
检查镍介导的肺癌发生的分子事件的整合。
澄清这些问题将提供关于MEG3作为预后生物标志物和/或作为
治疗目标最终,这两种用途都可以改善肺癌患者的临床结果。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Max Costa其他文献
Max Costa的其他文献
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{{ truncateString('Max Costa', 18)}}的其他基金
Persistent transcriptional changes induced by nickel through epigenetic alterations
镍通过表观遗传改变诱导持续转录变化
- 批准号:
10077549 - 财政年份:2020
- 资助金额:
$ 27.75万 - 项目类别:
Persistent transcriptional changes induced by nickel through epigenetic alterations
镍通过表观遗传改变诱导持续转录变化
- 批准号:
9899647 - 财政年份:2020
- 资助金额:
$ 27.75万 - 项目类别:
Persistent transcriptional changes induced by nickel through epigenetic alterations
镍通过表观遗传改变诱导持续转录变化
- 批准号:
10515635 - 财政年份:2020
- 资助金额:
$ 27.75万 - 项目类别:
Persistent transcriptional changes induced by nickel through epigenetic alterations
镍通过表观遗传改变诱导持续转录变化
- 批准号:
10294236 - 财政年份:2020
- 资助金额:
$ 27.75万 - 项目类别:
Arsenic and Nickel Carcinogenesis in Human Lung Cells
砷和镍对人肺细胞的致癌作用
- 批准号:
10470848 - 财政年份:2019
- 资助金额:
$ 27.75万 - 项目类别:
Arsenic carcinogenesis and disruption of histone variant H3.3 assembly
砷致癌和组蛋白变体 H3.3 组装的破坏
- 批准号:
10407027 - 财政年份:2019
- 资助金额:
$ 27.75万 - 项目类别:
Arsenic and Nickel Carcinogenesis in Human Lung Cells
砷和镍对人肺细胞的致癌作用
- 批准号:
10004646 - 财政年份:2019
- 资助金额:
$ 27.75万 - 项目类别:
Arsenic carcinogenesis and disruption of histone variant H3.3 assembly
砷致癌和组蛋白变体 H3.3 组装的破坏
- 批准号:
10631227 - 财政年份:2019
- 资助金额:
$ 27.75万 - 项目类别:
Arsenic and Nickel Carcinogenesis in Human Lung Cells
砷和镍对人肺细胞的致癌作用
- 批准号:
10681242 - 财政年份:2019
- 资助金额:
$ 27.75万 - 项目类别:
Arsenic and Nickel Carcinogenesis in Human Lung Cells
砷和镍对人肺细胞的致癌作用
- 批准号:
10245059 - 财政年份:2019
- 资助金额:
$ 27.75万 - 项目类别:
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