A large body of evidence shows that
p16(INK4a) overexpression predicts improved survival and increased radiosensitivity in HPV-mediated oropharyngeal
squamous cell carcinomas.(OPSCC). Here we demonstrate that the presence of transcriptionally active HPV16 in oral cavity
squamous cell carcinomas does not correlate with
p16(INK4a) overexpression, enhanced local
tumor immunity, or improved outcome. It is interesting that HPV-mediated oropharyngeal
squamous cell carcinomas can be categorized as having a 'nonaggressive' invasion phenotype, whereas aggressive invasion phenotypes are more common in HPV-negative
squamous cell carcinomas. We have developed primary
cancer cell lines from resections with known pattern of invasion as determined by our validated risk model. Given that cell lines derived from HPV-mediated oropharyngeal
squamous cell carcinomas are less invasive than their HPV-negative counterparts, we tested the hypothesis that viral
oncoproteins E6, E7, and
p16(INK4a) can affect
tumor invasion. Here we demonstrate that
p16(INK4a) overexpression in two
cancer cell lines (UAB-3 and UAB-4), derived from oral cavity
squamous cell carcinomas with the most aggressive invasive phenotype (worst pattern of invasion type 5 (WPOI-5)), dramatically decreases
tumor invasiveness by altering expression of extracellular matrix remodeling genes. Pathway analysis integrating changes in
RNA expression and
kinase activities reveals different potential p16(INK4a)-sensitive pathways. Overexpressing
p16(INK4a) in UAB-3 increases EGFR activity and increases MMP1 and MMP3 expression, possibly through STAT3 activation. Overexpressing
p16(INK4a) in UAB-4 decreases PDGFR gene expression and reduces MMP1 and MMP3, possibly through STAT3 inactivation. Alternatively, ZAP70/Syk might increase MUC1 phosphorylation, leading to the observed decreased MMP1 expression.