# MECHANISM OF HEXAVALENT CHROMIUM CARCINOGENESIS ROLE OF LONG NON-CODING RNA DYSREGULATION

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $362,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Hexavalent chromium [Cr(VI)] is a common and well-recognized environmental carcinogen causing lung and other
cancers, however, the mechanism of Cr(VI) carcinogenesis remains elusive. Previous Cr(VI) carcinogenesis
studies mostly focus on its genotoxic effects. However, studies showed that Cr(VI) exposure also causes non-
genotoxic effects such as epigenetic changes as evidenced by dysregulations in DNA methylation and histone
posttranslational modifications. While these observations open new directions for studying Cr(VI) carcinogenesis, it
remains to be determined how Cr(VI)-caused epigenetic dysregulations contribute to Cr(VI) carcinogenesis.
Moreover, very little is known about the role of non-coding RNAs (ncRNAs) especially the long non-coding RNAs
(lncRNAs), another epigenetic mechanism regulating gene expression, in Cr(VI) carcinogenesis. Recent studies
show that lncRNAs are emerging key regulators of gene expression and play critical roles in cancer. The goal of
this study is to investigate the mechanism of Cr(VI) carcinogenesis focusing on the role of lncRNA dysregulation.
Our preliminary studies found: (i) Chronic Cr(VI) exposure increases the expression of the lncRNA ABHD11-AS1,
which contributes causally to Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property and
tumorigenesis; (ii) Chronic Cr(VI) exposure down-regulates the expression of miR-182-5p; but knockdown of
ABHD11-AS1 increases the level of miR-182-5p. Moreover, overexpressing miR-182-5p in Cr(VI)-transformed cells
significantly reduces their transformed phenotypes, phenocopying the effect of ABHD11-AS1 knockdown; (iii) The
Rho GTPase Rac1 and Erk1/2 MAPK are highly activated in Cr(VI)-transformed cells; (iv) The expression level of
the oncogenic Rac-GEF Tiam1 is significantly up-regulated in Cr(VI)-transformed cells; but overexpressing miR-
182-5p or knockdown of ABHD11-AS1 greatly decrease Tiam1 level; (v) The expression level of PARP-1, a critical
DNA repair gene and a key regulator of gene expression, is significantly up-regulated in Cr(VI)-transformed cells;
(vi) The level of protein PARylation is drastically increased in Cr(VI)-transformed cells; inhibition of PARP-1 or
knockdown of PARP-1 greatly decrease the levels of protein PARylation and ABHD11-AS1 and the transformed
phenotype of Cr(VI)-transformed cells. Based on literature review and our novel preliminary data, our central
hypothesis is: “Chronic Cr(VI) exposure-upregulated lncRNA ABHD11-AS1 sponges miR-182-5p and causes its
down-regulation, which leads to increased level of the oncogenic Rac-GEF Tiam1 promoting Cr(VI)
carcinogenesis”. Three aims are proposed: Aim 1 will determine the mechanism by which chronic Cr(VI) exposure
up-regulates ABHD11-AS1. Aim 2 will demonstrate that ABHD11-AS1 sponges miR-182-5p causing its down-
regulation and promoting Cr(VI)-exposure-induced CSC-like property, cell transformation and tumorigenesis. And
Aim 3 will demonstrate that down-...

## Key facts

- **NIH application ID:** 10372591
- **Project number:** 7R01ES029942-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Chengfeng Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,250
- **Award type:** 7
- **Project period:** 2021-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372591

## Citation

> US National Institutes of Health, RePORTER application 10372591, MECHANISM OF HEXAVALENT CHROMIUM CARCINOGENESIS ROLE OF LONG NON-CODING RNA DYSREGULATION (7R01ES029942-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10372591. Licensed CC0.

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