Urinary-type plasminogen activator receptor/alpha 3 beta 1 integrin signaling, altered gene expression, and oral tumor progression.
Oral squamous cell carcinoma (OSCC) has 50% 5-year survival rate, highlighting our limited understanding of the molecular events that contribute to disease progression. Microarray analyses of primary oral tumors have identified urinary-type plasminogen activator (uPA) and its receptor (uPAR) as key genes associated with human OSCC progression. The uPAR functions as both a proteinase receptor and an integrin ligand, modifying proteolysis, migration, integrin signaling, and cellular transcription. In the current study, uPAR expression levels were modified in OSCC cells followed by analysis of tumor growth in an in vivo orthotopic xenograft model and by transcriptional profiling. Overexpression of uPAR resulted in more infiltrative and less differentiated tumors, with ill-defined borders, cytologic atypia, and enhanced vascularity. Analysis of serial sections of both murine experimental tumors and microarrayed human OSCC showed a statistically significant association between uPAR and alpha(3) integrin colocalization in areas exhibiting extracellular signal-regulated kinase phosphorylation, suggesting that uPAR/alpha(3) integrin interaction potentiates extracellular signal-regulated kinase signaling in vivo. This is supported by cDNA microarray analysis, which showed differential expression of 148 genes (113 upregulated and 35 downregulated). Validation of gene expression changes in human OSCC using immunohistochemistry and quantitative real-time PCR showed increased growth factors, proteinases/inhibitors, and matrix components in uPAR-overexpressing tumors. Together, these results support a model wherein increased uPAR expression promotes alpha(3)beta(1) integrin association, resulting in increased mitogen-activated protein kinase signaling and transcriptional activation, leading to the formation of more aggressive tongue tumors. This combined approach has efficacy to identify additional biomarkers and/or prognostic indicators associated with aggressive human OSCC.
Department of Surgery, Northwestern University Feinberg Medical School, Chicago, Illinois, USA.
Supurna
S
Ghosh
Jennifer
J
Koblinski
Jeffrey
J
Johnson
Yueying
Y
Liu
Aaron
A
Ericsson
J Wade
JW
Davis
Zonggao
Z
Shi
Matthew J
MJ
Ravosa
Susan
S
Crawford
Shellaine
S
Frazier
M Sharon
MS
Stack
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D039201:Integrin alpha3beta1 / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D010447:Peptide Hydrolases / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014183:Transplantation, Heterologous
D014408:Biomarkers, Tumor; D016326:Extracellular Matrix Proteins; D039201:Integrin alpha3beta1; D036341:Intercellular Signaling Peptides and Proteins; D055293:Receptors, Urokinase Plasminogen Activator; D048049:Extracellular Signal-Regulated MAP Kinases; D010447:Peptide Hydrolases