Non-melanoma skin cancer (NMSC) includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which together are the most common type of human malignancy. More than one million Americans develop one or more of these tumors annually and BCCs represent more than 75% of NMSC. Thus BCCs are a major public health problem and a major cause of morbidity and escalating health care costs in this country. Environmental exposure to solar ultraviolet B (UVB) is the major risk factor for the induction of BCCs. The molecular basis underlying the development of these tumors is now known to relate to mutations in the hedgehog signaling pathway including patched (PTCH). sonic hedgehog (SHH) and smoothened (SMO). In addition, an animal model for BCCs. the patched heterozygous knockout mouse, has been developed which provides a system with which to explore the molecular pathogenesis of UVB-induced BCCs. It is known that skin exposure to UVB drives a proliferative stimulus to epidermal keratinocytes and that induction of the enzyme ornithine decarhoxylase (ODC') is a major contributor to the augmented growth and clonal expansion of initiated cells. UVB exposure also enhances oxidant stress in the skin. which is accompanied by increased generation of reactive oxygen species (ROS) that can induce ODC and augment keratinocyte proliferation. In this proposal we will test the hypothesis that factors which enhance cell proliferation such as increased ODC expression and oxidant stress are crucial for UVB induction of BCCs. We have developed a novel modification of patch +/- heterozygous mice in which ODC is overexpressed (ptch +I-/ODC TgN). These mice have accelerated spontaneous development of microscopic BCCs like tumors by the age of 20 weeks and with UVB exposure visible BCCs within 30 weeks. We will utilize this animal model to probe the pathogenesis of IJVB-induced BCCs by assessing the role of over-expression of ODC, by evaluating the effects of altered cell cycle regulation and by measuring oxidant stress. The result of these studies will be used to devise innovative pharmacogenetic approaches to the chemoprevention of UVB-induced BCCs. It is likely that novel anti-carcinogenic agents potentially suitable for testing in the human population could be identified as a result of the studies in this proposal.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097249-02
Application #
6616070
Study Section
Special Emphasis Panel (ZRG1-PTHB (03))
Program Officer
Okano, Paul
Project Start
2002-07-23
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$344,382
Indirect Cost
Name
Columbia University (N.Y.)
Department
Dermatology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Kim, Kwang Ho; Back, Jung Ho; Zhu, Yucui et al. (2011) Resveratrol targets transforming growth factor-?2 signaling to block UV-induced tumor progression. J Invest Dermatol 131:195-202
Rezvani, Hamid Reza; Kim, Arianna L; Rossignol, Rodrigue et al. (2011) XPC silencing in normal human keratinocytes triggers metabolic alterations that drive the formation of squamous cell carcinomas. J Clin Invest 121:195-211
Athar, Mohammad; Back, Jung Ho; Kopelovich, Levy et al. (2009) Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms. Arch Biochem Biophys 486:95-102
Tang, Xiuwei; Kim, Arianna L; Kopelovich, Levy et al. (2008) Cyclooxygenase-2 inhibitor nimesulide blocks ultraviolet B-induced photocarcinogenesis in SKH-1 hairless mice. Photochem Photobiol 84:522-7
Tang, Xiuwei; Zhu, Yucui; Han, Lydia et al. (2007) CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice. J Clin Invest 117:3753-64
Athar, Mohammad; Back, Jung Ho; Tang, Xiuwei et al. (2007) Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol 224:274-83
Athar, Mohammad; Tang, Xiuwei; Lee, Juliette L et al. (2006) Hedgehog signalling in skin development and cancer. Exp Dermatol 15:667-77
Bickers, David R; Athar, Mohammad (2006) Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol 126:2565-75
Kim, Arianna L; Zhu, Yucui; Zhu, Huijie et al. (2006) Resveratrol inhibits proliferation of human epidermoid carcinoma A431 cells by modulating MEK1 and AP-1 signalling pathways. Exp Dermatol 15:538-46
Lee, Juliette Lois; Kim, Arianna; Kopelovich, Levy et al. (2005) Differential expression of E prostanoid receptors in murine and human non-melanoma skin cancer. J Invest Dermatol 125:818-25

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