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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：
Max Costa
金额：
$ 41.77万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
https://reporter.nih.gov/project-details/10004646
关键词：
A549 AT Rich Sequence Address Adult Anchorage-Independent Growth Arsenic Attenuated Automobile Driving Binding Binding Proteins Bone Development CRISPR/Cas technology Carcinogens Categories Cell Nucleus Cells ChIP-seq Chemicals Chromatin Loop Cytoskeleton DNA DNA Sequence Development Down-Regulation Embryo Embryonic Development Epithelial Cells Event Exposure to Genes Glandular Cell Grant Homologous Gene Human In Vitro Incidence Knock-out Lamins Lead Lentivirus Vector Lower Gastrointestinal Tract Lung Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Matrix Attachment Regions Mediating Messenger RNA Metal Carcinogenesis Metals MicroRNAs Nickel Normal tissue morphology Nuclear Envelope Nuclear Matrix Nuclear Matrix-Associated Proteins Nuclear Pore Nuclear Proteins Nude Mice Paper Pathway interactions Play Post-Translational Protein Processing Process Protein Family Proteins Regulation Role Sampling Shapes Structure Tissues Translations Up-Regulation Work cancer cell cancer type carcinogenesis carcinogenicity cell transformation cellular engineering craniofacial development experimental study falls gene repression inhibitor/antagonist knock-down mRNA Stability member migration mimetics neurodevelopment osteoblast differentiation overexpression p38 Mitogen Activated Protein Kinase prevent protein expression transcription factor tumor tumorigenesis

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