title: The protective effect of p16(INK4a) in oral cavity carcinomas: p16(Ink4A) dampens tumor invasion-integrated analysis of expression and kinomics pathways.
abstract: 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.
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Isayeva
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Cancer Prevention and Control Program, Fox Chase Cancer Center, Temple University Health, Philadelphia, PA, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Ragin
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Dai
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tiffiny
authors.initials: T
authors.lastname: Cooper
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: William
authors.initials: W
authors.lastname: Carroll
authors.affiliation: The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Dayan
authors.affiliation: The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Marilena
authors.initials: M
authors.lastname: Vered
authors.affiliation: Department of Pathology, Beth Israel Medical Center, Continuum Health Partners, New York, NY, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Wenig
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Eben
authors.initials: E
authors.lastname: Rosenthal
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: William
authors.initials: W
authors.lastname: Grizzle
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Willey
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
authors.affiliation: Departments of Pathology, Surgery, Medicine, Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Brandwein-Gensler
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D009361:Neoplasm Invasiveness; D030361:Papillomavirus Infections; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16