Integrative Genomics in Combination with RNA Interference Identifies Prognostic and Functionally Relevant Gene Targets for Oral Squamous Cell Carcinoma

被引:17
作者
Xu, Chang [1 ,2 ]
Wang, Pei [3 ,4 ]
Liu, Yan [3 ]
Zhang, Yuzheng [3 ]
Fan, Wenhong [3 ]
Upton, Melissa P. [5 ]
Lohavanichbutr, Pawadee [3 ]
Houck, John R. [3 ]
Doody, David R. [3 ]
Futran, Neal D. [1 ]
Zhao, Lue Ping [3 ,4 ]
Schwartz, Stephen M. [3 ,6 ]
Chen, Chu [1 ,3 ,6 ]
Mendez, Eduardo [1 ,2 ,7 ]
机构
[1] Univ Washington, Dept Otolaryngol Head & Neck Surg, Seattle, WA 98195 USA
[2] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA
[3] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA
[4] Univ Washington, Dept Biostat, Seattle, WA 98195 USA
[5] Univ Washington, Dept Pathol, Seattle, WA 98195 USA
[6] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA
[7] VA Puget Sound Hlth Care Syst, Surg & Perioperat Care Serv, Seattle, WA USA
来源
PLOS GENETICS | 2013年 / 9卷 / 01期
基金
美国国家卫生研究院;
关键词
GTPASE-ACTIVATING PROTEIN; BREAST-CANCER METASTASIS; DNA COPY NUMBER; BINDING-PROTEIN; EXPRESSION; HEAD; SURVIVAL; P53; GROWTH; CHEMOTHERAPY;
D O I
10.1371/journal.pgen.1003169
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
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页数:13
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