Combined TP53 mutation/3p loss correlates with decreased radiosensitivity and increased matrix-metalloproteinase activity in head and neck carcinoma.

TitleCombined TP53 mutation/3p loss correlates with decreased radiosensitivity and increased matrix-metalloproteinase activity in head and neck carcinoma.
Publication TypeJournal Article
Year of Publication2015
AuthorsRaju SC, Hauff SJ, Lemieux AJ, Orosco RK, Gross AM, Nguyen LT, Savariar E, Moss W, Whitney M, Cohen EE, Lippman SM, Tsien RY, Ideker T, Advani SJ, Nguyen QT
JournalOral Oncol
Volume51
Issue5
Pagination470-5
Date Published2015 May
ISSN1879-0593
Abstract

OBJECTIVE: Patients 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/METHODS: TP53 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).

RESULTS: Radiotherapy 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<0.01). There was no difference in cisplatin sensitivity between the cell lines.

CONCLUSIONS: TP53 mutation combined with FHIT deletion correlates with decreased radiosensitivity in HNC cell lines. Xenograft from "double-hit" cells exhibit increased MMP-2/9 activity. These findings may in part account for the worse clinical outcome seen in patients with HNSCC "double-hit" tumors.

DOI10.1016/j.oraloncology.2015.01.014
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/25735654?dopt=Abstract
Alternate JournalOral Oncol.
PubMed ID25735654
PubMed Central IDPMC4427339
Grant ListES014811 / ES / NIEHS NIH HHS / United States
GM085764 / GM / NIGMS NIH HHS / United States
P30CA023100 / CA / NCI NIH HHS / United States
R01 CA158448 / CA / NCI NIH HHS / United States
R01 EB014929 / EB / NIBIB NIH HHS / United States
RR031979 / RR / NCRR NIH HHS / United States
T32 DC000028 / DC / NIDCD NIH HHS / United States
T32 DC000028 / DC / NIDCD NIH HHS / United States
Track(s): 
Bioinformatics and Systems Biology