The goal of this proposal is to understand the inhibitory mechanism of IKKalpha in IKKalpha-mediated tumor development in skin carcinogenesis. Our recent results showed that Ikkalpha+/- mice developed twice more benign tumors, papillomas, and ten times more malignant carcinomas than Ikkalpha+/+ mice did in skin carcinogenesis. The patterns and levels of IKKalpha expression were well-correlated to stages of tumor development. Importantly, Ikkalpha+/- carcinomas lost the wildtype allele. Regardless of Ikkalpha genotypes, poorly differentiated carcinomas lost IKKalpha, indicating that loss of IKKalpha is associated with tumor formation and malignant carcinoma development in skin carcinogenesis. To investigate whether the increased expression of IKKalpha inhibits tumor development, we generated epidermis-specific IKKalpha transgenic mice. Our preliminary results showed that these mice were resistant to tumor progression. To investigate the mechanism of the IKKalpha inhibitory function on tumor development, we plan to: 1) Determine the inhibitory effect of IKKalpha on tumor development by using transgenic mice expressing different forms of IKKalpha in epidermis. To determine the mechanism of the inhibitory effect of IKKalpha on tumor development, we will generate the transgenic mice expressing the kinase inactive (KA) and the C-terminal deletion (C80, a stronger differentiation ability) forms of IKKalpha and determine their abilities in repressing tumor development by using the two-step and complete skin carcinogenesis protocols. 2) Determine the mechanisms of the inhibitory effect of IKKalpha on tumor development. Based on our findings, the mechanisms of IKKalpha-mediated tumor development includes the elevated mitogenic activity, such as Erk, TGFalpha, EGF, VEGF-A, IL-1alpha and TNFalpha, and the genomic instability, such as deregulating expression of multiple genes, including nucleophosmin (NPM) and 14-3-3sigma that are involved in chromosome duplication, DNA repair, and cell cycle control. We will determine whether overexpressed IKKalpha in skin regulates these elements or other IKKalpha target genes to inhibit tumor development. In addition, we will investigate how tumor cells bypass IKKalpha to develop carcinomas, because IKKalpha transgenic mice still developed some malignant carcinomas. This proposed study will further provide an outline of the inhibitory mechanism of IKKalpha and evaluate whether IKKalpha can be a potential candidate for preventing skin tumor development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA117314-01
Application #
7001038
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (M1))
Program Officer
Steele, Vernon E
Project Start
2005-07-15
Project End
2007-06-30
Budget Start
2005-07-15
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$75,000
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
Liu, Shuang; Chen, Zhisong; Zhu, Feng et al. (2012) I?B kinase alpha and cancer. J Interferon Cytokine Res 32:152-8
Park, Eunmi; Liu, Bigang; Xia, Xiaojun et al. (2011) Role of IKK? in skin squamous cell carcinomas. Future Oncol 7:123-34
Liu, B; Willette-Brown, J; Liu, S et al. (2011) IKK? represses a network of inflammation and proliferation pathways and elevates c-Myc antagonists and differentiation in a dose-dependent manner in the skin. Cell Death Differ 18:1854-64
Xia, Xiaojun; Park, Eunmi; Liu, Bigang et al. (2010) Reduction of IKKalpha expression promotes chronic ultraviolet B exposure-induced skin inflammation and carcinogenesis. Am J Pathol 176:2500-8
Liu, Bigang; Zhu, Feng; Xia, Xiaojun et al. (2009) A tale of terminal differentiation: IKKalpha, the master keratinocyte regulator. Cell Cycle 8:527-31
Zhu, Feng; Park, Eunmi; Liu, Bigang et al. (2009) Critical role of IkappaB kinase alpha in embryonic skin development and skin carcinogenesis. Histol Histopathol 24:265-71
Liu, Bigang; Xia, Xiaojun; Zhu, Feng et al. (2008) IKKalpha is required to maintain skin homeostasis and prevent skin cancer. Cancer Cell 14:212-25
Park, Eunmi; Zhu, Feng; Liu, Bigang et al. (2007) Reduction in IkappaB kinase alpha expression promotes the development of skin papillomas and carcinomas. Cancer Res 67:9158-68
Zhu, Feng; Xia, Xiaojun; Liu, Bigang et al. (2007) IKKalpha shields 14-3-3sigma, a G(2)/M cell cycle checkpoint gene, from hypermethylation, preventing its silencing. Mol Cell 27:214-27
Liu, Bigang; Park, Eunmi; Zhu, Feng et al. (2006) A critical role for I kappaB kinase alpha in the development of human and mouse squamous cell carcinomas. Proc Natl Acad Sci U S A 103:17202-7