Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling.
Gene expression profiling was conducted using primary human nasopharyngeal carcinoma (NPC) biopsy samples to improve the understanding of the molecular pathways defining NPC and to identify novel potential therapeutic targets. RNA samples were extracted from 36 patients suspected to have NPC and hybridized onto the Affymetrix U133A chip. NPC was diagnosed in 19 patients, 11 had lymphoid hyperplasia (LH), and 6 were "normal" biopsies. Clinical stages for these NPC patients ranged from I-IV, including one M1. All NPC patients (except the M1) were treated with curative intent, which included radiotherapy alone (4 patients), or combined with chemotherapy (14 patients). Unsupervised clustering demonstrated a distinct NPC expression pattern, compared to normal biopsies. Subsequent Significance Analysis of Microarrays (SAM) derived from 14 NPC and 6 normal samples discovered 1,089 differentially regulated genes. Pathway analyses revealed novel insights into the mechanisms leading to NPC, whereby upregulation of NFkappaB2 and survivin play central roles in increasing resistance to apoptosis, and changes in integrin and WNT/beta-catenin signaling leading to uncontrolled proliferation. The role of survivin in resisting apoptosis in NPC was confirmed by RNA interference. Our data provide novel insights into the development and progression of NPC, and suggest survivin as a novel therapeutic target for NPC.
Shi
Wei
W
Division of Applied Molecular Oncology, Ontario Cancer Institute, Toronto, Canada.
Bastianutto
Carlo
C
Li
Anna
A
Perez-Ordonez
Bayardo
B
Ng
Raymond
R
Chow
Kan-Yan
KY
Zhang
Wendy
W
Jurisica
Igor
I
Lo
Kwok-Wai
KW
Bayley
Andrew
A
Kim
John
J
O'Sullivan
Brian
B
Siu
Lillian
L
Chen
Eric
E
Liu
Fei-Fei
FF
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D016023:Integrins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077022:Survivin; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D016023:Integrins; D008869:Microtubule-Associated Proteins; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; D009363:Neoplasm Proteins; D000077022:Survivin; D051153:Wnt Proteins; D051176:beta Catenin