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Chromium in carcinogenesis and angiogenesis

Award Number: R01ES027901
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: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Chromium in carcinogenesis and angiogenesis - Hexavalent chromium [Cr(VI)] long-term exposure is associated with human lung cancer. Although there is emerging interest in the mechanism underlying Cr(VI)-induced carcinogenesis, the mechanism and role of Cr(VI) in inducing carcinogenesis still remains to be elucidated. In preliminary studies, we used human peripheral blood mononuclear cells (PBMC cells) from Cr(VI) exposed and control subjects to perform whole genome expression array analysis, and found that IL-8 and CXCL5 are the two most up-regulated genes detected in the exposure group compared with non-exposure subjects. We validated our findings by RT-qPCR and ELISA assay. Additionally, we found that miR-199a suppression and β-catenin upregulation are important for IL-8 and CXCL5 induction. Forced expression of miR-199a and knockdown of IL-8 or CXCL5 inhibited both cell transformation and angiogenesis. These findings are consistent with our results obtained from Cr(VI)- transformed cells and from in vitro studies. Furthermore, we found that β-catenin directly activated IL-8 expression at transcriptional level, while miR-199a directly targets hypoxia-inducible factor 1 (HIF-1) for inhibiting HIF-1 expression. We hypothesize that miR-199a suppression and β-catenin upregulation are important in Cr(VI)-induced tumorigenesis and angiogenesis through induction of IL- 8 and CXCL5 expression. Tumor cell growth and angiogenesis are the important characteristics of carcinogenesis, transformation from normal cells to cancer cells. In order to test this hypothesis, we will perform three specific aims: Aim 1) To determine role of miR-199a suppression and β-catenin upregulation in Cr(VI)-induced cell transformation, and identify the mechanism of IL-8 and CXCL5 elevation. Aim 2) To determine roles of miR-199a, β-catenin, IL-8, and CXCL5 in Cr(VI) transformed cell-induced tumor growth. Aim 3) To determine whether Cr-T cells induce tumor angiogenesis through IL-8 receptors using chimeric tumor model and determine expression levels of IL-8, CXCL5, β-catenin, and miR-199a in peripheral blood mononuclear cells (PBMCs) and plasma, and the possible correlations with Cr(VI) internal exposure doses in workers with occupational Cr(VI) exposure. We will use a combination of molecular approaches, a n animal model, and blood and tissue samples from human subjects to define roles and mechanisms of miR-199a, β- catenin, IL-8, and CXCL5 in Cr(VI)-induced cell transformation, tumor growth, and angiogenesis. These studies will not only help us understand the underlying mechanisms of Cr(VI) in inducing carcinogenesis, but also identify potential new biomarkers for early detection of Cr(VI) exposure of workers in electroplating factories in the future.


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 = -$536 )
2026	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Environmental Health	000	6	11/18/2025	NON-COMPETING CONTINUATION	-$536
														Subtotal = -$536

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Environmental Health	000	6	6/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $337,440 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Environmental Health	001	6	8/24/2022	NON-COMPETING CONTINUATION	$337,440
2022	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Environmental Health	000	5	8/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $337,440

Issue Date FY: 2021 ( Subtotal = $337,440 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Environmental Health	002	5	7/8/2021	NON-COMPETING CONTINUATION	$337,440
2021	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Environmental Health	001	4	2/26/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$307,764
2021	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Environmental Health	005	4	7/18/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$150,353
2021	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Environmental Health	004	3	7/18/2021	NON-COMPETING CONTINUATION	-$1
2021	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Environmental Health	000	3	2/25/2021	NON-COMPETING CONTINUATION	-$307,764
2021	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Environmental Health	003	2	7/18/2021	NON-COMPETING CONTINUATION	-$150,352
														Subtotal = $337,440

Issue Date FY: 2020 ( Subtotal = $307,765 )
2020	2020	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Environmental Health	000	3	7/2/2020	NON-COMPETING CONTINUATION	$307,765
														Subtotal = $307,765

Issue Date FY: 2019 ( Subtotal = $307,765 )
2019	2019	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Environmental Health	000	2	7/18/2019	NON-COMPETING CONTINUATION	$307,765
														Subtotal = $307,765

Issue Date FY: 2018 ( Subtotal = $320,890 )
2018	2018	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Environmental Health	000	1	6/25/2018	NEW	$320,890
														Subtotal = $320,890

Grand Total All Awards = $1,610,764

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Chromium in carcinogenesis and angiogenesis

Award Number: R01ES027901

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: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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