The invasive behavior of oral carcinoma requires coordinated cellular events including basement membrane attachment and detachment, extracellular matrix (ECM) proteolysis, and acquisition of motility. Altered expression of matrix binding integrins is associated with oral carcinoma progression. Integrins can promote an hierarchy of cellular responses dictated by the physical nature of the integrin engagement, thereby transducing distinct signals from the ECM. Production of two distinct classes of ECM-degrading proteinases, plasminogen activators (PA) and matrix metalloproteinases (MMP) is also in early event in malignant progression. The correlation between enhanced expression of the serine proteinase urinary-type PA (uPA or urokinase), MMP-9 (gelatinase B) and tumor progression is well described. Binding of urinary type-PA (uPA) o its cellular receptor (uPAR) leads to enhanced pericellular plasmin formation, which in turn directly degrades ECIV giycoproteins and activates selected MMPs such as MMP-9. Moreover, uPAJR may also regulate invasive behavior via novel, proteinase-independent mechanisms, by modifying integrin adhesive functions and modulating integrin signaling pathways. Our data demonstrate that a3b1 integrin aggregation alters expression of both uPA and MMP-9. Further, a3bl integrin aggregation induces uPA/R/a3b 1 integrin association and MAP kinase (MAPK) activation, resulting in enhance( proteinase transcription Based on these results, it is the working hypothesis of this proposal that a functional link between adhesion and proteolysis regulates oral carcinoma invasive behavior. Specifically we propose a multi-functional interaction of the uPA/R system with carcinoma cell integrins, such that integrin-in edited adhesion modulates cellular, iPA expression, while subsequent uPA/uPAR/integrin interactions in turn regulate downstream adhesive events that control proteinase expression, proliferation, adhesion and motility. To test this hypothesis, we will assess the specific physical parameters of a3b1 integrin engagement that control proteinase induction. The ability of uPAIR to modulate a3b1 signaling and modify proteinase expression and proliferation will then be analyzed. Immunohistochemical and biochemical analysis of normal and tumor tissues will be employed to evaluate integrin, proteinase, and MAPK expression and activity. The functional contribution of induced proteinases to the cellular invasive phenotype will then be evaluated. The long term goal of the proposed research is to provide a more detailed understanding of the functional link between adhesion and proteolysis and the con tribution of this in terplay to regulation of metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA085870-01A2
Application #
6370838
Study Section
Pathology B Study Section (PTHB)
Program Officer
Jhappan, Chamelli
Project Start
2001-06-01
Project End
2005-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$231,525
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Johnson, Jeff J; Miller, Daniel L; Jiang, Rong et al. (2016) Protease-activated Receptor-2 (PAR-2)-mediated Nf-?B Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma. J Biol Chem 291:6936-45
Shah, Sunny S; Senapati, Satyajyoti; Klacsmann, Flora et al. (2016) Current Technologies and Recent Developments for Screening of HPV-Associated Cervical and Oropharyngeal Cancers. Cancers (Basel) 8:
Slouka, Zdenek; Senapati, Satyajyoti; Shah, Sunny et al. (2015) Integrated, DC voltage-driven nucleic acid diagnostic platform for real sample analysis: Detection of oral cancer. Talanta 145:35-42
Shi, Zonggao; Johnson, Jeffrey J; Jiang, Rong et al. (2015) Decrease of miR-146a is associated with the aggressiveness of human oral squamous cell carcinoma. Arch Oral Biol 60:1416-27
Miller, Daniel L; Davis, J Wade; Taylor, Kristen H et al. (2015) Identification of a human papillomavirus-associated oncogenic miRNA panel in human oropharyngeal squamous cell carcinoma validated by bioinformatics analysis of the Cancer Genome Atlas. Am J Pathol 185:679-92
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
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
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
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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