# New Mechanism of Arsenic Carcinogenesis

> **NIH NIH K02** · UNIVERSITY OF IOWA · 2020 · $14,836

## Abstract

Long-term human exposure to inorganic arsenic induces lung, skin, bladder and liver cancer. The molecular
mechanisms of arsenic-induced carcinogenesis remain to be elucidated. Our preliminary studies show that
long-term exposure to arsenic induces EGFR via miR-370 suppression, which activates PKM2 and NF-κB; and
induces PKM2 expression via downregulation of miR-199a expression and Nrf2 overexpression. HIF-1α is also
a direct target of miR-199a. PKM2 interacts with p65 and HIF-1α to activate NF-κB and HIF-1 signaling. We
further demonstrated that arsenic-transformed (As-T) lung epithelial cells form tumors in vivo and secrete
factors CXCL8 and CXCL5, the downstream effectors of PKM2, to activate angiogenesis. We have established
a novel chimeric tumor model to study the crosstalk of signaling molecules in As-T cells and human endothelial
cells in regulating tumor angiogenesis. We hypothesize that arsenic induces PKM2 expression via miR-370
/miR-199a suppression and Nrf2 upregulation for inducing cell transformation, tumor growth and angiogenesis.
To test this hypothesis, three aims are proposed: Aim 1 will investigate the mechanism of PKM2 activation and
upregulation induced by arsenic treatment, and determine the role of PKM2 in oncogenic signaling pathway.
Aim 2 will investigate the role and mechanism of PKM2 pathway in arsenic-induced cell transformation and
tumor growth. Aim 3 will investigate the role and mechanism of PKM2 in mediating interactions of As-T cells
and endothelial cells and in regulating tumor angiogenesis. This K02 will help foster the candidate’s ability to
achieve these research goals by providing her with protected time to be fully engaged in her career
development to become an excellent independent investigator in the field of Environmental Health Science
(EHS). She has obtained American Cancer Society Research Scholar Grant to investigate the role and
mechanisms of Cr(VI)-induced carcinogenesis and whether miRNAs such as miR-143 and cytokines such as
IL-6 can be used as biomarkers for early detection and prevention of chronic Cr(VI) exposure-related adverse
health effects using population study. This K02 will also allow her to focus on studying new mechanism of
arsenic in inducing tumorigenesis through PKM2 signaling pathway. Her career development plan involves
intense training in techniques and analysis in metal-related carcinogenesis, which will enhance her knowledge
and skills in this area. The K02 will be of critical value to expand the candidate’s research program with the
potential to discover novel mechanisms of arsenic carcinogenesis that may pave the way to prevent chronic
arsenic exposure-caused carcinogenesis by interrupting the novel signaling pathway.

## Key facts

- **NIH application ID:** 9892010
- **Project number:** 5K02ES029119-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Ling-Zhi Liu
- **Activity code:** K02 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $14,836
- **Award type:** 5
- **Project period:** 2018-04-01 → 2020-07-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892010

## Citation

> US National Institutes of Health, RePORTER application 9892010, New Mechanism of Arsenic Carcinogenesis (5K02ES029119-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9892010. Licensed CC0.

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