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
SATB2的表达在金属癌变过程中起关键作用。SATB2是唯一一个上调的常见基因
多种致癌金属对BEAS2B细胞的转化及SATB2基因在正常BEAS2B细胞中的表达
防止金属致癌。在砷(As)或镍(Ni)转化的细胞中敲除SATB2,导致
转化特征的丧失,包括锚定独立生长,增强的细胞侵袭和
迁移。SATB2的调控涉及miR-31和miR23a。Runx2转录因子下调
镍和砷暴露引起的抑制SATB2表达和增加RUNX2的miRNAs
通过减弱这些翻译抑制miR的表达间接诱导SATB2。实现以下目标的机制
砷镍诱导的RUNX2在砷镍转化细胞中的表达
将会被研究。Runx2的激活似乎是一个关键的上游事件,它会增加SATB2蛋白,
保持癌症的特征。Runx2将在正常BEAS2B中被敲除以研究其在SATB2表达中的作用
镍、砷诱导的细胞转化作用。MiR-31和miRNA23a的Runx2和异构体
并对BEAS2B转化的发生率进行了评估。这些稍后的实验将解决
这些miRNA如何阻止SATB2 mRNA的翻译。我们将使用RUNX2的化学抑制剂(A1-10-
104)研究镍、砷诱导的细胞转化和过表达RUNX2转化的细胞
是被压制的。A1-10-104还将用于研究其对裸鼠异种移植瘤形成的影响。我们
将使用RUNX2芯片序列来识别用As和Ni处理的细胞或由它们转化的细胞中的下游靶点
金属,以及在过表达RUNX2的细胞中。SATB2 Chip-Seq将调查这是如何
转录因子保持癌症的特征。我们将在样本中研究RUNX2/miRNA/SATB2轴
人类肺癌及其周围的正常组织。我们将研究镍和砷暴露的机制
诱导BEAS2B细胞转化,增加并维持高水平的RUNX2 mRNA和蛋白以及
维护激活RUNX2所需的翻译后修改。如何实现的机制
Runx2下调miRNA-31和23a将被调查。我们将研究是否给予miR-
慢病毒载体中的模拟物(miRNA-31或23a)可以缩小BEAS2B诱导的原位或异种移植瘤
AS、Ni或高表达SATB2的转化细胞与A549肺癌细胞相比
低水平的SATB2。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Max Costa其他文献
Max Costa的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
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:
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:
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:
相似海外基金
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
- 批准号:
18K16115 - 财政年份:2018
- 资助金额:
$ 41.77万 - 项目类别:
Grant-in-Aid for Early-Career Scientists