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Abstract
In oral squamous cell carcinoma (OSCC), metastasis to lymph nodes is associated with a 50% reduction in 5-year survival. To identify a metastatic gene set based on DNA copy number abnormalities (CNAs) of differentially expressed genes, we compared DNA and RNA of OSCC cells laser-microdissected from non-metastatic primary tumors (n = 17) with those from lymph node metastases (n = 20), using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR)<5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Of these, 114 were found to have a significant correlation between DNA copy number and gene expression (FDR<0.01). Among these 114 correlated transcripts, the corresponding genomic regions of each of 95 transcripts had CNAs differences between primary and metastatic OSCC (FDR<0.01). Using an independent dataset of 133 patients, multivariable analysis showed that the OSCC–specific and overall mortality hazards ratio (HR) for patients carrying the 95-transcript signature were 4.75 (95% CI: 2.03–11.11) and 3.45 (95% CI: 1.84–6.50), respectively. To determine the degree by which these genes impact cell survival, we compared the growth of five OSCC cell lines before and after knockdown of over-amplified transcripts via a high-throughput siRNA–mediated screen. The expression-knockdown of 18 of the 26 genes tested showed a growth suppression ≥30% in at least one cell line (P<0.01). In particular, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC, and the growth suppression was likely caused by increase in apoptosis. Further investigation is warranted to examine the biological role of these genes in OSCC progression and their therapeutic potentials.
Highlights
Metastatic spread to the cervical lymph nodes is a major feature associated with tumor aggressiveness in oral squamous cell carcinoma (OSCC), reducing 5-year survival by about 50% [1,2,3]
Among the 20 OSCC patients with lymph node metastasis, eight had cancers arising in the oropharynx, while the remaining carcinomas arose from the oral cavity
Of the 17 non-metastatic primary OSCC patients, three had primary tumors that arose in the oropharynx, and the remaining tumors were from the oral cavity
Summary
Metastatic spread to the cervical lymph nodes is a major feature associated with tumor aggressiveness in oral squamous cell carcinoma (OSCC), reducing 5-year survival by about 50% [1,2,3]. For these patients, treatment intensification with radiation and chemotherapy results in improved survival outcomes Cooper [4]. There is an urgent need to better understand the mechanism underlying the lymphotropism of OSCC tumor cells and to develop specific, less toxic therapies to target this event. DNA microarray-based transcriptome profiling has been proven an effective tool for the identification of Author Summary
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