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Elucidating the molecular signaling of Cadmium Carcinogenesis

Award Number: R01ES033657
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: 06/02/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Elucidating the molecular signaling of Cadmium Carcinogenesis - Project Summary/Abstract Cadmium (Cd) is a known human carcinogen and risk factor for prostate cancer (CaP). The human prostate is composed of three anatomic zones, namely the peripheral zone (PZ), transition zone (TZ), and central zone (CZ). CaP arises primarily in the PZ of the prostate and followed by the TZ. Our in vivo studies suggest that Cd-exposure induced different types of prostate malignances such as, Squamous cell carcinoma (SCC) in TZ and poorly differentiated carcinoma (PDC) in PZ of the prostate. Hence, the goal of the study is to understand the pathobiology and the molecular landscape of Cd-induced SCC in laboratory models (in vitro and in vivo) and clinical specimens. Chronic exposure of plasma concentrations of Cd in TZ of prostate cells formed tumors (SCC) in xenotransplanted mice that differed from Cd-induced tumors (PDC) in the PZ of the prostate. Subsequent, analysis of the mechanism of action revealed that Cd exposure induced the expression of zinc- finger of the cerebellum 2 (ZIC2) in the benign prostate hyperplasia (BPH: TZ) cells but not in RWPE-1 (PZ) cells. At a molecular level, ZIC2 interacts with glioma-associated oncogene family zinc finger 1 (GLI1), a downstream target of sonic hedgehog (Shh) signaling, which activates the pro-survival machinery in Cd- exposed BPH1 cells. Similarly, overexpression of ZIC2 in RWPE-1 cells resulted in spheroid formation, confirming the oncogenic function of ZIC2. Also, we found ZIC2, and GLI1 expressions were correspondingly increased in different grades of CaP as compared to BPH or adjacent healthy tissue (Chandrasekaran et al.,2020 Oncogenesis). Based on these results, we hypothesize that the activation of ZIC2 and GLI1 is responsible for the malignant transformation (SCC) of Cd exposed BPH cells. Aim 1: Dissect the mechanism by which Cd activates ZIC2 and determine whether ZIC2 activation is essential for the malignant transformation of BPH1 & BPH/hTERT1 cells. Aim-2: Determine the molecular interplay between ZIC2 and GLI1 activation and examine their function in Cd exposed BPH1 & BPH/hTERT1 cells. Aim 3: Study Cd- induced tumorigenesis in mouse models and validate molecular markers in human CaP specimens. The successful completion of the studies will not only contribute new information towards filling the lacunae of knowledge regarding the pathobiology of Cd-induced SCC, but also provide an insight into the molecular mechanisms (MTF-1, ZIC2 and GLI1 signaling) pertaining to SCC as well as other metal induced malignances.


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: 2025 ( Subtotal = $0 )
2025	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Environmental Health	000	3	3/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $485,844 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Environmental Health	000	3	3/28/2024	NON-COMPETING CONTINUATION	$485,844
														Subtotal = $485,844

Issue Date FY: 2023 ( Subtotal = $499,532 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Environmental Health	000	2	3/13/2023	NON-COMPETING CONTINUATION	$499,532
														Subtotal = $499,532

Issue Date FY: 2022 ( Subtotal = $510,684 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Environmental Health	000	1	6/2/2022	NEW	$510,684
														Subtotal = $510,684

Grand Total All Awards = $1,496,060

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Elucidating the molecular signaling of Cadmium Carcinogenesis

Award Number: R01ES033657

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: 06/02/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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