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Combined TP53 mutation/3p loss correlates with decreased radiosensitivity and increased matrix-metalloproteinase activity in head and neck carcinoma.
- Source :
-
Oral Oncology . May2015, Vol. 51 Issue 5, p470-475. 6p. - Publication Year :
- 2015
-
Abstract
- Summary 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 13688375
- Volume :
- 51
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Oral Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 101931442
- Full Text :
- https://doi.org/10.1016/j.oraloncology.2015.01.014