# Alternative splicing in arsenical skin carcinogenesis

> **NIH NIH R21** · UNIVERSITY OF LOUISVILLE · 2020 · $234,000

## Abstract

Project Summary
Chronic exposure to arsenic, most commonly through contaminated drinking water, plagues over 200 million
individuals in over 70 countries including the USA. Arsenic is a multi-organ toxicant and chronic arsenic
exposure causes several chronic diseases including cancer in multiple organs, skin cancer being the most
common. While several mechanisms are postulated to be responsible for arsenic-induced carcinogenesis, a
clear picture is yet to emerge. It is well known that chronic arsenic exposure radically changes the
transcriptomic and proteomic signatures, but the underlying mechanism for such sweeping global changes
are not yet clearly understood. Differential alternative splicing plays a role in carcinogenesis and may be at
play in arsenic-induced carcinogenesis. We employed state-of-the-art RNA-Seq analysis in
a well-established model of arsenic-induced skin cancer (HaCaT cells exposed continuously to 100 nM sodium
arsenite for 32 weeks) in a longitudinal study to understand the global changes in splicing occurring during the
transformation process. Our data indicate >600 differential alternative splicing events occurred at each of the
time points studied (7, 19, 28 weeks of exposure). This differential splicing program, by dramatically changing
the proteome, could be a key player in the arsenic-induced transformation of skin cells. The present proposal
aims to examine the contribution of significant differential splicing events at each time point towards the
process of carcinogenesis. We will specifically scrutinize if the significant splicing events predicted by our
transcriptomic studies can be correlated with protein isoform expression profiles. Furthermore, we also aim to
study if predicted significantly different spliced isoforms that take place in the 5' or 3' UTR of transcripts can
be correlated to expression profile in the mature mRNA samples from exposed and unexposed cells. The
outcomes from this study will further our understanding of how alternative splicing shapes the cellular events
taking place before, during and after the time the HaCaT cells become malignant. In addition, our study will
look to elaborate the mechanistic basis of how one change in an upstream regulatory alternative splicing factor
can cause genome-wide synchronized alternative splicing changes by signal amplification through successive
steps, leading to altered proteome and ultimately adverse health effects.

## Key facts

- **NIH application ID:** 9979035
- **Project number:** 1R21ES030334-01A1
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** J CHRISTOPHER STATES
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2020-07-14 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979035

## Citation

> US National Institutes of Health, RePORTER application 9979035, Alternative splicing in arsenical skin carcinogenesis (1R21ES030334-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979035. Licensed CC0.

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