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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Venkatachalam, Sundaresan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
Zip Code
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
Skinner, Heath D; Sandulache, Vlad C; Ow, Thomas J et al. (2012) TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence. Clin Cancer Res 18:290-300
Zhao, Mei; Sano, Daisuke; Pickering, Curtis R et al. (2011) Assembly and initial characterization of a panel of 85 genomically validated cell lines from diverse head and neck tumor sites. Clin Cancer Res 17:7248-64
Sano, Daisuke; Xie, Tong-Xin; Ow, Thomas J et al. (2011) Disruptive TP53 mutation is associated with aggressive disease characteristics in an orthotopic murine model of oral tongue cancer. Clin Cancer Res 17:6658-70
Younes, Maher N; Yigitbasi, Orhan G; Yazici, Yasemin D et al. (2007) Effects of the integrin-linked kinase inhibitor QLT0267 on squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 133:15-23
Ren, Xiaoyang; Xu, Zhengming; Myers, Jeffery N et al. (2007) Bypass NFkappaB-mediated survival pathways by TRAIL and Smac. Cancer Biol Ther 6:1031-5
Mandal, Mahitosh; Younes, Maher; Swan, Eric A et al. (2006) The Akt inhibitor KP372-1 inhibits proliferation and induces apoptosis and anoikis in squamous cell carcinoma of the head and neck. Oral Oncol 42:430-9