Mdig gene and histone demethylation in lung cancer
肺癌中的 Mdig 基因和组蛋白去甲基化
基本信息
- 批准号:8427387
- 负责人:
- 金额:$ 29.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-05-01 至 2016-02-28
- 项目状态:已结题
- 来源:
- 关键词:A549AccountingAcute Promyelocytic LeukemiaAffectAlveolar MacrophagesAmericanAreaBiological AssayBiological MarkersCarcinogensCell Culture TechniquesCell CycleCell Cycle ProgressionCell Cycle RegulationCell LineCell ProliferationCellsCessation of lifeCharacteristicsCyclinsDiseaseDown-RegulationDustEnvironmental CarcinogensEnvironmental HazardsEnvironmental and Occupational ExposureEpigenetic ProcessEpithelial CellsExperimental ModelsExposure toGene ActivationGene ExpressionGene Expression RegulationGenesGenomeGoalsHL-60 CellsHealthHeterochromatinHistone H3HistonesHumanIn VitroInterventionKnockout MiceLungLung diseasesLysineMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMeasuresMediatingMediator of activation proteinMethylationMineralsMolecularNamesNuclear AntigensNucleolar ProteinsNucleosomesNude MiceOccupationalOncogene ActivationOutcomePatientsPeptidesPhase TransitionPlayPrevention strategyPrincipal InvestigatorPrognostic MarkerProteinsRegimenRegulationRoleS PhaseSignal TransductionSmall Interfering RNASpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationStreamTestingTobacco smokingUnited StatesXenopus laevisattenuationbasecancer therapycancer typecdc Genescell growthcell growth regulationcell transformationdemethylationepigenetic markerexpectationimprovedinsightkillingsloss of functionlung cancer screeninglung carcinogenesismass spectrometermortalitynovel therapeutic interventionnovel therapeuticsoccupational hazardoutcome forecastresponsesmall hairpin RNAtherapeutic targettumorigenesistumorigenic
项目摘要
DESCRIPTION (provided by applicant): Lung cancer is the most common cancer worldwide, accounting for 1.3 million cancer deaths annually. Despite extensive efforts to elucidate mechanisms and develop new therapeutic regimens, the worldwide mortality rate of lung cancer remains high. Our long- term goal is to understand how mdig gene contributes to the initiation and progression of the human lung cancer and whether mdig can be served as a biomarker and a therapeutic target for lung cancer resulted from exposure to environmental or occupational hazards. The objective of this application is to investigate the role of Mdig protein played on the lung cell proliferation and carcinogenic transformation induced by environmental and occupational hazards/carcinogens. The central hypothesis is that Mdig promotes cell growth and transformation by functioning as a histone demethylase that antagonizes tri-methyl lysine 9 on histone H3. Down-regulation of tri-methyl lysine 9 of histone H3 will enhance the expression of genes associated with the cell cycle regulation and malignant transformation in lung epithelial cells. The rationale behind this proposal is that expression of mdig gene may be critical for lung cell proliferation and carcinogenic transformation in response to environmental carcinogens. To accomplish the objectives of this application, we will pursue three specific aims by using cell lines and nude mice as experimental models: (1) test the potential demethylase activity of mdig protein toward tri-methylated lysine 9 on histone H3; (2) determine whether the expression of the cell cycle-regulated genes, such as cyclins, Cdc25s and checkpoint proteins, is regulated by the methylation regulation of mdig; and (3) study the tumorigenic effect of mdig by both over- expression and down-regulation of mdig in BEAS-2B cells and A549 cells, respectively, in both cell culture and inoculation of the cells in nude mice. At the completion of these specific aims, we expect to have determined how mdig contributes to lung cell growth regulation and carcinogenic transformation in response to factors that cause lung cancer. We additionally expect, based on preliminary studies, that constitutive expression of mdig will compromise the tri-methylation of lysine 9 on histone H3, leading to attenuation of heterochromatin or the formation of other inhibitory epigenetic markers. As a result, the expression of genes associated with the cell cycle transition and cell proliferation will be enhanced. Finally, in addition to reveal a previously unknown new mechanism of the human lung cancer, it is anticipated that expression of mdig can be potentially served as a new biomarker and therapeutic target of the human lung cancer.
描述(由申请人提供):肺癌是全球最常见的癌症,每年占130万个癌症死亡。尽管为阐明机制和开发新的治疗方案而进行了广泛的努力,但肺癌的全球死亡率仍然很高。我们的长期目标是了解MDIG基因如何促进人类肺癌的开始和发展,以及MDIG是否可以用作生物标志物,以及暴露于环境或职业危害的肺癌的治疗靶标。该应用的目的是研究通过环境和职业危害/致癌物诱导的MDIG蛋白在肺部细胞增殖和致癌转化中的作用。中心假设是MDIG通过作为组蛋白脱甲基酶发挥作用,促进细胞的生长和转化,该脱甲基酶在组蛋白H3上拮抗三甲基赖氨酸9。组蛋白H3的三甲基赖氨酸9的下调将增强与细胞周期调节和肺上皮细胞中恶性转化相关的基因的表达。该提议背后的理由是,响应环境致癌物的肺部细胞增殖和致癌转化可能至关重要。为了实现此应用的目标,我们将通过使用细胞系和裸小鼠作为实验模型来追求三个特定目标:(1)测试MDIG蛋白在组蛋白H3上对三甲基化赖氨酸9的潜在脱甲基酶活性; (2)确定细胞周期调节的基因的表达(例如细胞周期蛋白,Cdc25s和检查点蛋白)是否受MDIG的甲基化调节调节; (3)分别研究MDIG在BEAS-2B细胞和A549细胞中MDIG的过度表达和下调的肿瘤效应,分别在细胞培养和裸鼠细胞的接种中。在完成这些特定目标时,我们希望确定MDIG如何促进肺细胞生长调节和致癌性转化,以响应导致肺癌的因素。我们还期望根据初步研究,MDIG的本构表达将损害组蛋白H3上赖氨酸9的三甲基化,从而导致异染色质的衰减或其他抑制性表观遗传标记的形成。结果,将增强与细胞周期过渡和细胞增殖相关的基因的表达。最后,除了揭示了人类肺癌的先前未知的新机制外,还可以预期MDIG的表达可以成为人类肺癌的新生物标志物和治疗靶标。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells.
- DOI:10.18632/oncotarget.1431
- 发表时间:2013-12
- 期刊:
- 影响因子:0
- 作者:Wu K;Chang Q;Lu Y;Qiu P;Chen B;Thakur C;Sun J;Li L;Kowluru A;Chen F
- 通讯作者:Chen F
Reactive oxygen species contribute to arsenic-induced EZH2 phosphorylation in human bronchial epithelial cells and lung cancer cells.
- DOI:10.1016/j.taap.2014.02.005
- 发表时间:2014-05-01
- 期刊:
- 影响因子:3.8
- 作者:Li, Lingzhi;Qiu, Ping;Chen, Bailing;Lu, Yongju;Wu, Kai;Thakur, Chitra;Chang, Qingshan;Sun, Jiaying;Chen, Fei
- 通讯作者:Chen, Fei
Increased expression of mdig predicts poorer survival of the breast cancer patients.
- DOI:10.1016/j.gene.2013.11.031
- 发表时间:2014-02-10
- 期刊:
- 影响因子:3.5
- 作者:Thakur C;Lu Y;Sun J;Yu M;Chen B;Chen F
- 通讯作者:Chen F
Paradoxical roles of mineral dust induced gene on cell proliferation and migration/invasion.
- DOI:10.1371/journal.pone.0087998
- 发表时间:2014
- 期刊:
- 影响因子:3.7
- 作者:Yu M;Sun J;Thakur C;Chen B;Lu Y;Zhao H;Chen F
- 通讯作者:Chen F
Carcinogenic metalloid arsenic induces expression of mdig oncogene through JNK and STAT3 activation.
- DOI:10.1016/j.canlet.2014.01.002
- 发表时间:2014-05-01
- 期刊:
- 影响因子:9.7
- 作者:Sun, Jiaying;Yu, Miaomiao;Lu, Yongju;Thakur, Chitra;Chen, Bailing;Qiu, Ping;Zhao, Hongwen;Chen, Fei
- 通讯作者:Chen, Fei
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Fei Chen其他文献
Fei Chen的其他文献
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{{ truncateString('Fei Chen', 18)}}的其他基金
Spatial genomic tools to interrogate T cell clonotypes, tumor clones and the microenvironment
用于询问 T 细胞克隆型、肿瘤克隆和微环境的空间基因组工具
- 批准号:
10565141 - 财政年份:2023
- 资助金额:
$ 29.56万 - 项目类别:
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10435281 - 财政年份:2021
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Arsenic-Induced miRNA-199 and mriRNA-214 Deplete Mitochondrial DNA for the Generation of Cancer Stem-Like Cells
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10489836 - 财政年份:2021
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10316248 - 财政年份:2021
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$ 29.56万 - 项目类别:
Arsenic-Induced miRNA-199 and mriRNA-214 Deplete Mitochondrial DNA for the Generation of Cancer Stem-Like Cells
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Reduced Reactive Oxygen Species and Oxidative Phosphorylation in Arsenic-Induced Cancer Stem Cells
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10441939 - 财政年份:2021
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Dissecting Nrf2-dependent HIF1a activation mechanism in arsenic-induced cancer stem-like cells
剖析砷诱导的癌症干细胞样细胞中 Nrf2 依赖性 HIF1a 激活机制
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10515655 - 财政年份:2021
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