# Mechanism for arsenic induced carcinogenesis

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2020 · $413,059

## Abstract

Abstract
Chromosomal instability (CIN) contributes to carcinogenesis by promoting aneuploidy. Arsenic is well known to
induce aneuploidy, however the molecular mechanism by which arsenic induces aneuploidy-mediated
carcinogenesis is yet to be delineated. We have identified a miRNA (hsa-miR-186) that is overexpressed in
arsenic-induced squamous cell carcinoma and that induces CIN when overexpressed in human keratinocytes.
This miRNA is encoded within intron 9 of the ZRANB2 gene and is co-transcribed as part of the ZRANB2
transcript. Such embedded microRNAs are processed out of the intronic RNA by the microRNA maturation
machinery. ZRANB2 encodes an alternative splicing factor containing two zinc fingers each with four-cysteines
coordinating the zinc. These types of zinc fingers are targets for arsenite displacement of zinc. We hypothesize
that chronic arsenic exposure disrupts ZRANB2 function by displacing zinc from the zinc fingers; cellular
homeostatic mechanisms induce ZRANB2 transcription; coincident increased hsa-miR-186 leads to CIN
contributing to arsenic-induced carcinogenesis. This project will determine the role of hsa-miR-186 in arsenic
induced CIN in human keratinocytes, and how ZRANB2 structure and function are modulated by arsenic
exposure. The following specific aims will be pursued to test this hypothesis: 1. Determine role of hsa-miR-186
in carcinogenic transformation of immortalized keratinocytes (HaCaT cells).; 2. Determine mechanism of
arsenite disruption of ZRANB2 structure and function; 3. Determine potential of hsa-miR-186 over-expression
to induce chromosomal instability and potential of arsenite to inhibit ZRANB2 directed splicing in primary
keratinocytes. Successful completion of these aims will demonstrate a novel mechanism for epigenetic
response to the environmental stress of arsenic exposure and demonstrate that this response causes
chromosomal instability (CIN) linked to arsenic-induced skin carcinogenesis. This mechanism likely plays a
role in arsenic-induced carcinogenesis in other organs as well. Thus, hsa-miR-186 could be a biomarker for
arsenic induced internal cancers in arsenic exposed patients. Demonstration of arsenite-exposure disturbance
of mRNA splicing patterns will open a new area of research into mechanisms of arsenic induced disease.

## Key facts

- **NIH application ID:** 9981741
- **Project number:** 5R01ES027778-04
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** J CHRISTOPHER STATES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $413,059
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981741

## Citation

> US National Institutes of Health, RePORTER application 9981741, Mechanism for arsenic induced carcinogenesis (5R01ES027778-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981741. Licensed CC0.

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