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

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

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:
    $ 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:

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
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