Genes and molecular pathways related to radioresistance of oral squamous cell carcinoma cells

Abstract

To identify genes associated with radioresistant oral squamous cell carcinoma (OSCC), we compared gene expression signatures between OSCC cell lines exhibiting radioresistance and cells with radiosensitivity after X-ray irradiation in a dose-dependent manner using Affymetrix GeneChip analysis with Human Genome-U133 plus 2.0 GeneChip. The microarray data identified 167 genes that were significantly overexpressed in radioresistant cells after X-ray irradiation. Among the genes identified, 40 were mapped to 3 highly significant genetic networks identified by the Ingenuity Pathway Analysis tool. Gene ontology analysis showed that cancer-related function had the highest significance. The 40 genes included 25 cancer-related genes that formed 1 network and were categorized by function into growth and proliferation, apoptosis, and adhesion. Furthermore, real-time quantitative reverse transcriptase-polymerase chain reaction showed that the mRNA expression levels of the 25 genes were higher in radioresistant cells than in radiosensitive cells in a dose-dependent manner and in a time-dependent manner. Our results suggest that the identified genes help to elucidate the molecular mechanisms of the radioresistance of OSCC and could be radiotherapeutic molecular markers for choosing the appropriate radiotherapy for this disease. ' 2007 Wiley-Liss, Inc.

Network-based analysis of calcium-binding protein genes identifies Grp94 as a target in human oral carcinogenesis

“…We recently developed the strategy of using a knowledge-based network approach to search for candidate genes relevant to the treatment of oral cancers (Kasamatsu et al, 2005;Higo et al, 2006;Ishigami et al, 2007). Thus, this study aimed to explore further the global changes in Ca 2 þ -binding protein genes associated with OSCCs by applying network development tools to expand on microarray analysis methods.…”

Targeting fibroblast growth factor receptor 3 enhances radiosensitivity in human squamous cancer cells

“…These findings strongly suggested the oncogenic properties of the FGFR3-mutated receptor. FGFR3, an elevated mRNA expression level of which was detected in radioresistant human SCC cell lines in our previous study (Ishigami et al, 2007), was found to be a candidate for radioresistant enhancements in SCC cells using microarray analysis. A more recent study also reported a relationship between FGFR3 and radiation sensitivity in artificially FGFR3-reduced oral SCC cells …”

“…Although previous studies have reported an association between enhanced radiosensitivity in oral SCC and certain gene expression (Shintani et al, 2003;Ishigami et al, 2007), to the best of our knowledge, the current report is the first on the use of the combination of an FGFR3 inhibitor and radiation in vitro and in vivo. Finally, the current data supported the idea that combination therapy with radiation and an FGFR3 inhibitor increases the therapeutic efficacy of radiation in human cancers including SCCs.…”

“…To verify whether the FGFR3 gene is associated with radioresistance in vitro, we performed an small interfering RNA (siRNA) experiment to inhibit expression of FGFR3 in the HSC-2 (radioresistant) cell line, in which we previously reported that expression of FGFR3 was higher than in the HSC-3 (radiosensitive) cell line (Ishigami et al, 2007). A series of cell growth experiments was performed to determine the effect of FGFR3 siRNA on the growth of the cancer cell lines.…”

“…Recently, our microarray analysis combined with the Ingenuity Pathway Analysis identified six genes (ID1, ID3, FGFR3, PEG10, ICAM2 and MMP13) associated with significant increases in radioresistant cells compared with radiosensitive cells in a dose-dependent and a time-dependent manner (Ishigami et al, 2007). Of them, results with the fibroblast growth factor receptor 3 (FGFR3) gene, whose receptors regulate proliferation, differentiation, migration and apoptosis (Johnson and Williams, 1993;Friesel and Maciag, 1995), emphasized the association with radioresistance based on the results of canonical pathway analysis, suggesting that the FGFR3 gene may disclose the molecular mechanisms of the radioresistance of squamous cell carcinomas (SCCs) that could be radiotherapeutic molecular markers for choosing the appropriate radiotherapy for this disease.…”