Squamous cell carcinoma of the oral cavity (SCCOC) is the sixth leading cause of cancer deaths worldwide. However, little is known about the cellular and molecular mechanisms of SCCOC tumor progression. In the prior funding period, we demonstrated that acquisition of anoikis-resistance is an important hallmark of oral epithelial tumor progression. Results of our cDNA microarray expression analysis of anoikis-resistant and - sensitive cells revealed that the S100A7 protein, a low-molecular-weight (11.4 kDa) Ca2+binding protein that belongs to S100 multigenic protein family, is differentially expressed in anoikis-sensitive and -resistant cells. Further analyses indicated that S100A7 is overexpressed in pre-invasive, well-differentiated SCCOC. However, with the progression to invasive carcinomas, S100A7 expression is often down-regulated or diminished in the late stages of tumorigenesis. While it is evident that S100A7 protein is critical to the tumorigenesis of certain cancers, it remains unclear whether S100A7 plays an """"""""oncogenic"""""""" or """"""""tumor suppressive"""""""" role in SCCOC given its biphasic expression. Our preliminary results show that despite its overexpression in premalignant oral lesions, S100A7 plays an important inhibitory role in SCCOC progression by down-regulating tumor growth, EMT, tumor invasion/metastasis at least in part through its role as a """"""""novel"""""""" regulator of 2-catenin degradation. Thus, the central hypothesis of this application is that S100A7 plays an important role as a """"""""tumor suppressor"""""""" in SCCOC development and progression, through its inhibition of cell proliferation, motility, EMT, and invasion by inhibition of 2-catenin, Twist, and Snail. This hypothesis will be tested in 4 specific aims, and it is our expectation that completion of the approaches outlined in these 4 aims will help us to define S100A7's role as a tumor suppressor in SCCOC and that this information will enhance our ability to clinically stage SCCOC and identify potential new targets for therapy.

Public Health Relevance

In the prior funding period, we demonstrated that acquisition of resistance to a specific form of cell death is an important hallmark of oral cancer growth. These studies led us to explore the function of a specific protein, S100A7, which is a low-molecular-weight calcium-binding protein that is more highly expressed in early staged cancers of the head and neck, with diminished expression in more advanced cancers. In the studies proposed here, we will better define the role of this protein in the growth of oral cancer, a leading cause of cancer deaths in the U.S. and around the world, in order to identify better ways to stage and treat this often deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014613-07
Application #
7797583
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Venkatachalam, Sundaresan
Project Start
2002-04-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$369,716
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Surgery
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Jin; Xie, Tongxin; Wang, Bingbing et al. (2017) PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions. Cancer Prev Res (Phila) 10:684-693
Tanaka, Noriaki; Zhao, Mei; Tang, Lin et al. (2017) Gain-of-function mutant p53 promotes the oncogenic potential of head and neck squamous cell carcinoma cells by targeting the transcription factors FOXO3a and FOXM1. Oncogene :
Coaxum, Sonya D; Tiedeken, Jessica; Garrett-Mayer, Elizabeth et al. (2017) The tumor suppressor capability of p53 is dependent on non-muscle myosin IIA function in head and neck cancer. Oncotarget 8:22991-23007
Zhou, Ge; Liu, Zhiyi; Myers, Jeffrey N (2016) TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response. J Cell Biochem 117:2682-2692
Osman, Abdullah A; Monroe, Marcus M; Ortega Alves, Marcus V et al. (2015) Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence. Mol Cancer Ther 14:608-19
Neskey, David M; Osman, Abdullah A; Ow, Thomas J et al. (2015) Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer. Cancer Res 75:1527-36
Fitzgerald, A L; Osman, A A; Xie, T-X et al. (2015) Reactive oxygen species and p21Waf1/Cip1 are both essential for p53-mediated senescence of head and neck cancer cells. Cell Death Dis 6:e1678
Osman, Abdullah A; Neskey, David M; Katsonis, Panagiotis et al. (2015) Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients. Cancer Res 75:1205-15
Zhou, Ge; Wang, Jiping; Zhao, Mei et al. (2014) Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation. Mol Cell 54:960-74
Xie, Tong-Xin; Zhou, Ge; Zhao, Mei et al. (2013) Serine substitution of proline at codon 151 of TP53 confers gain of function activity leading to anoikis resistance and tumor progression of head and neck cancer cells. Laryngoscope 123:1416-23

Showing the most recent 10 out of 17 publications