Tuesday, January 6, 2026 1/6/2026

Mechanism of Hexavalent Chromium Carcinogenesis Role of Long Non-Coding RNA Dysregulation

Award Number: R01ES029942
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Mechanism of Hexavalent Chromium Carcinogenesis Role of Long Non-Coding RNA Dysregulation - 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-regulation of miR-182-5p increases levels of the oncogenic Rac-GEF Tiam1 promoting Cr(VI)-exposure-induced CSC-like property, cell transformation and tumorigenesis. Tiam1 knockout mice will be used to demonstrate that Tiam1 plays an important role in Cr(VI)-induced lung carcinogenesis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$1,803 )
2026	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	000	5	11/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1,803
														Subtotal = -$1,803

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	001	5	12/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$354,990
2024	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	000	4	12/5/2023	NON-COMPETING CONTINUATION	-$354,990
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $358,875 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	001	5	5/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$358,875
2023	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	000	4	5/24/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $358,875

Issue Date FY: 2022 ( Subtotal = $362,250 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	002	4	7/8/2022	NON-COMPETING CONTINUATION	$362,250
2022	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	001	3	12/3/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$303,911
2022	2020	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	2	12/3/2021	NON-COMPETING CONTINUATION	-$303,911
														Subtotal = $362,250

Issue Date FY: 2021 ( Subtotal = $362,250 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	001	3	8/31/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$362,250
2021	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	2	8/30/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $362,250

Issue Date FY: 2020 ( Subtotal = $344,250 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	2	5/14/2020	NON-COMPETING CONTINUATION	$344,250
														Subtotal = $344,250

Issue Date FY: 2019 ( Subtotal = $344,250 )
2019	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	1	8/27/2019	NEW	$344,250
														Subtotal = $344,250

Grand Total All Awards = $1,770,072

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Mechanism of Hexavalent Chromium Carcinogenesis Role of Long Non-Coding RNA Dysregulation

Award Number: R01ES029942

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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