Arsenic and Nickel Carcinogenesis in Human Lung Cells
砷和镍对人肺细胞的致癌作用
基本信息
- 批准号:10004646
- 负责人:
- 金额:$ 41.77万
- 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:2019-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:A549AT Rich SequenceAddressAdultAnchorage-Independent GrowthArsenicAttenuatedAutomobile DrivingBindingBinding ProteinsBone DevelopmentCRISPR/Cas technologyCarcinogensCategoriesCell NucleusCellsChIP-seqChemicalsChromatin LoopCytoskeletonDNADNA SequenceDevelopmentDown-RegulationEmbryoEmbryonic DevelopmentEpithelial CellsEventExposure toGenesGlandular CellGrantHomologous GeneHumanIn VitroIncidenceKnock-outLaminsLeadLentivirus VectorLower Gastrointestinal TractLungMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMatrix Attachment RegionsMediatingMessenger RNAMetal CarcinogenesisMetalsMicroRNAsNickelNormal tissue morphologyNuclear EnvelopeNuclear MatrixNuclear Matrix-Associated ProteinsNuclear PoreNuclear ProteinsNude MicePaperPathway interactionsPlayPost-Translational Protein ProcessingProcessProtein FamilyProteinsRegulationRoleSamplingShapesStructureTissuesTranslationsUp-RegulationWorkcancer cellcancer typecarcinogenesiscarcinogenicitycell transformationcellular engineeringcraniofacial developmentexperimental studyfallsgene repressioninhibitor/antagonistknock-downmRNA Stabilitymembermigrationmimeticsneurodevelopmentosteoblast differentiationoverexpressionp38 Mitogen Activated Protein Kinasepreventprotein expressiontranscription factortumortumorigenesis
项目摘要
PROJECT SUMMARY
SATB2 expression is critical for metal carcinogenesis. SATB2 is the only common gene that is upregulated in
BEAS2B cells transformed by various carcinogenic metals and knock-down of SATB2 in normal BEAS2B cells
prevents metal carcinogenesis. Knockdown SATB2 in arsenic (As) or nickel (Ni) transformed cells, results in the
loss in hallmarks of transformation including anchorage independent growth, enhanced cell invasion and
migration. The regulation of SATB2 involves miR-31 and miR23a. RUNX2 transcription factor down regulates
the miRNAs that inhibit SATB2 expression and increases in RUNX2 brought about by exposure to Ni and As
indirectly induces SATB2 by attenuating expression of these translation inhibitory miRs. The mechanisms for
the increase expression of RUNX2 induced following exposure to As and Ni, and in As or Ni transformed cells
will be studied. RUNX2 activation appears to be a critical upstream event that increases SATB2 protein which
maintains cancer hallmarks. RUNX2 will be knocked out in normal BEAS2B to study its role in SATB2 expression
and for cell transformation induced by Ni and As. RUNX2 and antogomers of miR-31 and miRNA 23a will be
overexpressed and the incidence of BEAS2B transformation assessed. These later experiments will address
how these miRNA block the translation of SATB2 mRNA. We will utilize a chemical inhibitor of RUNX2 (A1-10-
104) to study whether cell transformation induced by Ni and As and, cells transformed by overexpress RUNX2
is suppressed. A1-10-104 will also be used to study its effect on xenograph tumor formation in nude mice. We
will use RUNX2 Chip-Seq to identify downstream targets in cells treated with As and Ni or transformed by these
metals, as well as in cells engineered to overexpress RUNX2. SATB2 Chip-Seq will investigate how this
transcription factor maintains cancer hallmarks. We will investigate the RUNX2/miRNA/SATB2 axis in samples
of human lung cancers and surrounding normal tissue. We will study the mechanisms of how Ni and As exposure
induce BEAS2B cell transformation, increase and maintain high levels of RUNX2 mRNA and protein as well as
maintaining the post-translational modifications that are required to activate RUNX2. The mechanisms of how
RUNX2 downregulates miRNA-31 and 23a will be investigated. We will study whether administration of miR-
mimetics (miRNA-31or 23a) in lentivirus vectors, can shrink orthotopic or xenograph tumors induced by BEAS2B
cells transformed with As, Ni or with overexpressed SATB2, compared to A549 lung cancer cells that have
low levels of SATB2.
项目总结
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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Max Costa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:
$ 41.77万 - 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:
$ 41.77万 - 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:
$ 41.77万 - 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:
$ 41.77万 - 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:
$ 41.77万 - 项目类别:
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
- 批准号:
9852426 - 财政年份:2019
- 资助金额:
$ 41.77万 - 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:
$ 41.77万 - 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:
$ 41.77万 - 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:
$ 41.77万 - 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:
$ 41.77万 - 项目类别:
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Function of Special AT-Rich sequence binding protein 1 in B cells' tolerance
特殊 AT-Rich 序列结合蛋白 1 在 B 细胞耐受中的作用
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