Accumulating evidence indicates that the development of highly invasive skin tumors may require multiple mutations at different loci and that over-expression or repression of key regulatory genes can cooperate to influence the development of cancer. Solar ultraviolet B (UVB) induces the expression and activities of ornithine decarboxylase (ODC) and cyclooxygenase-2 (COX-2). ODC is the rate limiting enzyme for synthesis of polyamines, which are essential for the growth and differentiation of all cells. COX-2 expression leads to enhanced synthesis of prostaglandins (PGs), particularly PGE2 in the skin. We have developed genetically engineered murine models coupled with specific pharmacological approaches to show that both ODC and COX-2 over-expression in murine skin enhances the growth of non-melanoma skin cancers (NMSCs), and that down-regulation of ODC or COX-2 attenuates the growth of these tumors only partially. Human squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) both over- express ODC and COX-2. We and others have shown that their over-expression underlies the pathogenesis of NMSCs. SCCs show their high expression particularly at the interface where they invade normal tissue. However, in BCCs, which are locally invasive and metastasize only rarely, COX-2 expression occurs primarily in stromal cells, whereas ODC expression is also comparatively less prominent. In this project we will test the hypothesis that both pathways can cooperate in the pathogenesis of NMSCs and that their temporal and spatial regulation determines the tumor phenotype and progression to a malignant phenotype. Since both augmented COX-2-generated PGE2 and ODC-dependent polyamine overproduction lead to enhanced proliferation, migration and invasiveness of cells carrying mutations in known tumor suppressor genes including p53 and ptch that characterize NMSCs, the combined inhibition of these molecular targets could provide an entirely novel approach to the chemoprevention of this neoplasm. We also proposed to investigate the mechanism by which combined over expression of ODC and COX-2 can lead to the pathogenesis of an invasive tumor phenotype. It is anticipated that the information generated in these studies could be quickly translated into clinical trials employing the uniquely available high risk population at the University of Alabama Medical Center.

Public Health Relevance

Both COX-2 and ODC are consistently up-regulated during pathogenesis of non- melanoma skin cancers (NMSCs). However, blocking either one of these molecular targets only partially blocks the development of NMSCs. This proposal attempts to block both of these molecular targets to abrogate the pathogenesis of the most common human cancer, NMSCs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138998-02
Application #
8236878
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Jhappan, Chamelli
Project Start
2011-03-04
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$303,988
Indirect Cost
$96,488
Name
University of Alabama Birmingham
Department
Dermatology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Liu, Liang; Rezvani, Hamid Reza; Back, Jung Ho et al. (2014) Inhibition of p38 MAPK signaling augments skin tumorigenesis via NOX2 driven ROS generation. PLoS One 9:e97245
Elmets, Craig A; Ledet, Johnathan J; Athar, Mohammad (2014) Cyclooxygenases: mediators of UV-induced skin cancer and potential targets for prevention. J Invest Dermatol 134:2497-502
Athar, Mohammad; Li, Changzhao; Kim, Arianna L et al. (2014) Sonic hedgehog signaling in Basal cell nevus syndrome. Cancer Res 74:4967-75
Brouxhon, S M; Kyrkanides, S; Teng, X et al. (2014) Soluble E-cadherin: a critical oncogene modulating receptor tyrosine kinases, MAPK and PI3K/Akt/mTOR signaling. Oncogene 33:225-35
Pal, Harish Chandra; Sharma, Samriti; Strickland, Leah Ray et al. (2014) Fisetin inhibits human melanoma cell invasion through promotion of mesenchymal to epithelial transition and by targeting MAPK and NF?B signaling pathways. PLoS One 9:e86338
Hunt, Katherine M; Srivastava, Ritesh K; Elmets, Craig A et al. (2014) The mechanistic basis of arsenicosis: pathogenesis of skin cancer. Cancer Lett 354:211-9
Chaudhary, Sandeep C; Singh, Tripti; Talwelkar, Sarang S et al. (2014) Erb-041, an estrogen receptor-* agonist, inhibits skin photocarcinogenesis in SKH-1 hairless mice by downregulating the WNT signaling pathway. Cancer Prev Res (Phila) 7:186-98
Xu, Jianmin; Weng, Zhiping; Arumugam, Aadithya et al. (2014) Hair follicle disruption facilitates pathogenesis to UVB-induced cutaneous inflammation and basal cell carcinoma development in Ptch(+/-) mice. Am J Pathol 184:1529-40
Arumugam, Aadithya; Weng, Zhiping; Chaudhary, Sandeep C et al. (2014) Keratin-6 driven ODC expression to hair follicle keratinocytes enhances stemness and tumorigenesis by negatively regulating Notch. Biochem Biophys Res Commun 451:394-401
Chaudhary, Sandeep C; Singh, Tripti; Kapur, Puneet et al. (2013) Nitric oxide-releasing sulindac is a novel skin cancer chemopreventive agent for UVB-induced photocarcinogenesis. Toxicol Appl Pharmacol 268:249-55

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