1. Combined TP53 mutation/3p loss correlates with decreased radiosensitivity and increased matrix-metalloproteinase activity in head and neck carcinoma
- Author
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Raju, Sharat C, Hauff, Samantha J, Lemieux, Aaron J, Orosco, Ryan K, Gross, Andrew M, Nguyen, Linda T, Savariar, Elamprakash, Moss, William, Whitney, Michael, Cohen, Ezra E, Lippman, Scott M, Tsien, Roger Y, Ideker, Trey, Advani, Sunil J, and Nguyen, Quyen T
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Genetics ,Dental/Oral and Craniofacial Disease ,Acid Anhydride Hydrolases ,Carcinoma ,Squamous Cell ,Cell Line ,Tumor ,Chromosome Deletion ,Chromosomes ,Human ,Pair 3 ,Genes ,p53 ,Head and Neck Neoplasms ,Humans ,Matrix Metalloproteinases ,Mutation ,Neoplasm Proteins ,Radiation Tolerance ,Head and neck cancer ,TP53 mutation ,3p Deletion ,FHIT ,Matrix metalloproteinases ,"double-hit'' ,"single-hit'' ,Double-stranded DNA breaks ,RNA interference ,Radiosensitivity ,“double-hit” ,“single-hit” ,Dentistry ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
ObjectivePatients with head and neck squamous cell carcinoma (HNSCC) containing TP53 mutation and 3p deletion ("double-hit") have poorer prognosis compared to patients with either event alone ("single-hit"). The etiology for worse clinical outcomes in patients with "double-hit" cancers is unclear. We compared radiosensitivity of cell lines containing both TP53 mutations and deletion of Fragile Histidine Triad (FHIT, the gene most commonly associated with 3p deletion) to "single-hit" lines with only TP53 mutation. We compared radiosensitivity in a "single-hit" cell line with TP53 mutation converted to "double-hit" using RNA interference targeting FHIT. Finally, we compared matrixmetalloproteinase-2/9 (MMP-2/9) activity, a previously-established biomarker for tumor aggressiveness, in xenograft tumors derived from these cell lines.Materials/methodsTP53 mutation and FHIT deletion profiles of HNSCC lines were established using Cancer Cell Line Encyclopedia (CCLE). We used RNA-interference to convert a "single-hit" cell line (SCC4) to "double-hit". Cultured cells were examined for radiosensitivity and cisplatin sensitivity. MMP-2/9 activity was evaluated in "double-hit" versus "single-hit" tumors using ratiometric activatable cell-penetrating peptide (RACPP) in tongue (n=17) and flank xenografts (n=4).ResultsRadiotherapy caused greater double-stranded DNA breaks in "single-hit" vs naturally occurring and engineered "double-hit" cells. In-vivo, "double-hit" xenografts demonstrated higher MMP-2/9 activity compared to "single-hit" xenografts (p
- Published
- 2015