The primary aim of the proposed research is to determine the role of STATs, particularly STAT3, in mouse skin tumor promotion and multistage skin carcinogenesis. During the previous funding period, we found that certain STATs (signal transducers and activators of transcription) (i.e., STATs 1, 3, and 5) are activated in tumor promoter-treated epidermis, epidermis of K14.TGFalpha (transforming growth factor alpha) transgenic mice and epidermis of BK5.erbB2 transgenic mice. In addition, these same STAT family members are constitutively activated in skin papillomas generated by a DMBA-TPA two-stage carcinogenesis protocol. The mechanism for activation of STATs in both tumor promoter treated epidermis and in papillomas appears to be due to activation of the EGFr. In this revised renewal application, new preliminary data is provided using epidermis specific STAT3 deficient mice. These mice show a significantly reduced epidermal proliferative response following topical application of TPA. Thus, activation of STAT family members, and in particular STAT3, may play an important role in skin tumor promotion and multistage skin carcinogenesis. In the next funding period, we will test the hypothesis that STAT signaling, activated via EGFr/EGFr homodimers and/or EGFr/erbB2 heterodimers, is critical for the process of skin tumor promotion and for the development of autonomous growth in skin papillomas. Additionally, we will test the hypothesis that STAT3 activation mediates, in part, tumor promoter-induced epidermal hyperproliferation.
The Specific Aims are: 1) To generate transgenic mice with activated STAT3 (using a constitutively active form, STAT 3C) and examine their skin phenotype and their susceptibility to skin tumor promotion and multistage skin carcinogenesis; 2) Determine the impact of STAT3 deficiency on tumor promotion and multistage skin carcinogenesis; 3) Determine the functional consequences of STAT3 activation on proliferation/ differentiation of normal vs initiated (v-ras Ha)keratinocytes; and 4) To examine the STAT3 regulated genes in mouse epidermis contributing to skin tumor promotion and two-stage carcinogenesis. Successful completion of the studies proposed in this revised renewal application would establish STAT3 signaling as an important component of skin tumor promotion and tumor development in mouse skin. This would represent a significant advancement in our understanding of the mechanisms underlying tumor promotion by diverse agents and multistage skin carcinogenesis in general. Finally, the proposed studies could lead to the discovery of new targets for the chemoprevention of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076520-10
Application #
7234843
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Poland, Alan P
Project Start
1998-01-07
Project End
2009-05-06
Budget Start
2007-07-01
Budget End
2009-05-06
Support Year
10
Fiscal Year
2007
Total Cost
$302,817
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Srivastava, Jaya; Rho, Okkyung; Youssef, Ronnie M et al. (2016) Twist1 regulates keratinocyte proliferation and skin tumor promotion. Mol Carcinog 55:941-52
Rao, Dharanija; Macias, Everardo; Carbajal, Steve et al. (2015) Constitutive Stat3 activation alters behavior of hair follicle stem and progenitor cell populations. Mol Carcinog 54:121-33
Bozeman, Ronald; Abel, Erika L; Macias, Everardo et al. (2015) A novel mechanism of skin tumor promotion involving interferon-gamma (IFN?)/signal transducer and activator of transcription-1 (Stat1) signaling. Mol Carcinog 54:642-53
Lee, Hyunseung; Kim, Mihwa; Morales, Liza D et al. (2015) Constitutive activation of Stat3 in mouse epidermis is linked to hair deficiency and cytoskeletal network damage. Exp Dermatol 24:796-8
Macias, Everardo; Rao, Dharanija; Carbajal, Steve et al. (2014) Stat3 binds to mtDNA and regulates mitochondrial gene expression in keratinocytes. J Invest Dermatol 134:1971-1980
Yokogawa, Maki; Takaishi, Mikiro; Nakajima, Kimiko et al. (2013) Imiquimod attenuates the growth of UVB-induced SCC in mice through Th1/Th17 cells. Mol Carcinog 52:760-9
Macias, Everardo; Rao, Dharanija; Digiovanni, John (2013) Role of stat3 in skin carcinogenesis: insights gained from relevant mouse models. J Skin Cancer 2013:684050
Rho, Okkyung; Kim, Dae Joon; Kiguchi, Karou et al. (2011) Growth factor signaling pathways as targets for prevention of epithelial carcinogenesis. Mol Carcinog 50:264-79
Swindell, William R; Johnston, Andrew; Carbajal, Steve et al. (2011) Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis. PLoS One 6:e18266
Kim, Dae Joon; Tremblay, Michel L; Digiovanni, John (2010) Protein tyrosine phosphatases, TC-PTP, SHP1, and SHP2, cooperate in rapid dephosphorylation of Stat3 in keratinocytes following UVB irradiation. PLoS One 5:e10290

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