Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. The 5-year survival rate has remained at a low 50% for the past 20 years, highlighting our limited understanding of the molecular events that govern OSCC initiation, progression and metastasis. As the high mortality from OSCC is attributed to metastasis, a more detailed analysis of the molecular events that potentiate OSCC dissemination are a necessary prerequisite to the development of novel early detection and treatment strategies. Analysis of epigenetic changes associated with OSCC metastasis has identified loss of E-cadherin along with enhanced expression of urinary type plasminogen activator (uPA) and ?3 integrin as key candidate biomarkers for prediction of poor disease outcome. The proteinase uPA binds to a glycosylphosphatidyl inositol (GPI)-linked receptor, uPAR, whereupon it initiates zymogen activation cascades leading to proteolytic modification of basement membrane proteins, potentiating invasion and metastasis. Furthermore, results obtained during the previous funding period have identified a matrix- induced physical interaction between uPA/R and ?3?1 integrin that initiates a Src/MEK/ERK-dependent signaling pathway culminating in activation of the uPA promoter. In contrast to integrin signaling, activation of E-cadherin through formation of de novo junctions represses proteinase activity and invasion. Cross-talk between ?3?1 integrin and E-cadherin is evident, as integrin clustering downregulates surface E-cadherin, thereby destabilizing cell-cell junctional contacts. These data support the hypothesis that a functional link between adhesion and proteolysis regulates OSCC invasive behavior. Proposed experiments will elucidate mechanisms by which uPAR, as a lateral ?3?1 integrin ligand, can modulate ?3?1 signaling and thereby regulate OSCC metastatic behavior. Experiments proposed in Aim 1 will focus on matrix regulation of uPAR/?3?1 membrane dynamics to elucidate mechanisms whereby lipid raft partitioning of uPAR/?3?1 can regulate signal transduction and alter gene expression.
Aim 2 will evaluate the mechanisms by which uPAR modulates integrin-regulated changes in E-cadherin junctional integrity and activation of ?-catenin-mediated transcription in response to junction dissolution. These mechanistic data will be integrated in Aim 3 to assess epigenetic factors in OSCC progression using in vitro and in vivo model systems that more accurately reflect the in vivo microenvironment. Together these experiments will provide novel data on mechanisms whereby lateral interactions of uPAR with ?3?1 integrin contribute to OSCC tumor dissemination and may provide the rationale for long-term studies that target this interaction as a novel therapeutic strategy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085870-09
Application #
7763903
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
2000-04-01
Project End
2011-05-31
Budget Start
2010-03-01
Budget End
2011-05-31
Support Year
9
Fiscal Year
2010
Total Cost
$151,423
Indirect Cost
Name
University of Missouri-Columbia
Department
Pathology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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Johnson, Jeff; Shi, Zonggao; Liu, Yueying et al. (2014) Inhibitors of NF-kappaB reverse cellular invasion and target gene upregulation in an experimental model of aggressive oral squamous cell carcinoma. Oral Oncol 50:468-77
Miller, Daniel L; Puricelli, Michael D; Stack, M Sharon (2012) Virology and molecular pathogenesis of HPV (human papillomavirus)-associated oropharyngeal squamous cell carcinoma. Biochem J 443:339-53
Shi, Zonggao; Liu, Yueying; Johnson, Jeffrey J et al. (2011) Urinary-type plasminogen activator receptor (uPAR) modulates oral cancer cell behavior with alteration in p130cas. Mol Cell Biochem 357:151-61
Ravosa, Matthew J; Ning, Jie; Liu, Yueying et al. (2011) Bisphosphonate effects on the behaviour of oral epithelial cells and oral fibroblasts. Arch Oral Biol 56:491-8
Jiang, Rong; Shi, Zonggao; Johnson, Jeffrey J et al. (2011) Kallikrein-5 promotes cleavage of desmoglein-1 and loss of cell-cell cohesion in oral squamous cell carcinoma. J Biol Chem 286:9127-35

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