# Arsenic and Nickel Carcinogenesis in Human Lung Cells

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $401,008

## Abstract

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.

## Key facts

- **NIH application ID:** 10245059
- **Project number:** 5R01ES030572-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Max Costa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $401,008
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245059

## Citation

> US National Institutes of Health, RePORTER application 10245059, Arsenic and Nickel Carcinogenesis in Human Lung Cells (5R01ES030572-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245059. Licensed CC0.

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