Although arsenic is a known human carcinogen and induces cancers of the skin, lung, liver and bladder, the underlying carcinogenic mechanism(s) is not known. The US Environmental Protection Agency has placed arsenic at the top of its superfund contamination list. One of the main difficulties in studying mechanisms of arsenic carcinogenesis is the lack of a suitable human cell model whereby the various tumorigenic stages can be dissected and the molecular changes associated with each stage examined. While preliminary data obtained by the applicant has shown that arsenic can induce malignant transformation of papillomavirus-immortalized human bronchial epithelial (BEP2D) cells, this model is not ideal due to the presence of viral oncoproteins. The newly established telomerase (hTERT) -immortalized human bronchial epithelial (IMNHBE) cell transformation model that has normal p53 and p16 functions represents an attractive alternative to further ascertain the mechanism involved in arsenic-induced bronchial carcinogenesis. A series of cellular and molecular assays will be conducted using isolated clonal cell lines at each stage of the carcinogenic process to identify the necessary changes essential for arsenic carcinogenesis. The proposal has 2 main objectives: The first is to establish an in vitro human epithelial cell transformation model for arsenic carcinogenesis using two independent, telomerase-immortalized bronchial epithelial cell lines; and the second goal is to examine the mechanism(s) involved, particularly loss of tumor suppressor functions, associated with each stage of the carcinogenic process. A series of 7 specific aims are proposed to address 4 testable hypotheses. The IM NHBE cells are anchorage dependent and do not form tumors in immunosuppressed host animals. CDNA arrays coupled with functional analysis at the gene level will be conducted using tumors and cells from intermediate transformation stages to provide a mechanistic basis for arsenic-induced bronchial carcinogenesis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011804-04
Application #
6892083
Study Section
Special Emphasis Panel (ZRG1-PTHC (03))
Program Officer
Reinlib, Leslie J
Project Start
2002-07-12
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$367,875
Indirect Cost
Name
Columbia University (N.Y.)
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Pei, Hailong; Hu, Wentao; Guo, Ziyang et al. (2018) Long Noncoding RNA CRYBG3 Blocks Cytokinesis by Directly Binding G-Actin. Cancer Res 78:4563-4572
Hei, Tom K; Zhao, Yongliang; Zhou, Hongning et al. (2011) Mechanism of radiation carcinogenesis: role of the TGFBI gene and the inflammatory signaling cascade. Adv Exp Med Biol 720:163-70
Karasic, Thomas B; Hei, Tom K; Ivanov, Vladimir N (2010) Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: a new potential therapy for the treatment of melanoma. Exp Cell Res 316:1994-2007
Wen, G; Hong, M; Calaf, G M et al. (2010) Phosphoproteomic profiling of arsenite-treated human small airway epithelial cells. Oncol Rep 23:405-12
Ivanov, Vladimir N; Zhou, Hongning; Partridge, Michael A et al. (2009) Inhibition of ataxia telangiectasia mutated kinase activity enhances TRAIL-mediated apoptosis in human melanoma cells. Cancer Res 69:3510-9
Hei, Tom K; Ballas, Leslie K; Brenner, David J et al. (2009) Advances in radiobiological studies using a microbeam. J Radiat Res 50 Suppl A:A7-A12
Zhang, Ye; Wen, Gengyun; Shao, Genze et al. (2009) TGFBI deficiency predisposes mice to spontaneous tumor development. Cancer Res 69:37-44
Ivanov, Vladimir N; Partridge, Michael A; Johnson, Geoffrey E et al. (2008) Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression. Exp Cell Res 314:1163-76
Shao, Genze; Balajee, Adayabalam S; Hei, Tom K et al. (2008) p16INK4a downregulation is involved in immortalization of primary human prostate epithelial cells induced by telomerase. Mol Carcinog 47:775-83
Shah, Jinesh N; Shao, Genze; Hei, Tom K et al. (2008) Methylation screening of the TGFBI promoter in human lung and prostate cancer by methylation-specific PCR. BMC Cancer 8:284

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