Identification of cisplatin-resistance related genes in head and neck squamous cell carcinoma.
Resistance to cisplatin is a major obstacle to successful treatment of head and neck squamous cell carcinoma (HNSCC). To investigate the molecular mechanism of this resistance, we compared the gene expression profiles between the cisplatin-sensitive SCC cell lines (Sa-3, H-1 and KB) and the cisplatin-resistant cell lines established from them (Sa-3R, H-1R and KB-R) using Affymetrix U133 Plus 2.0 microarray. We identified 199 genes differentially expressed in each group. To identify important functional networks and ontologies to cisplatin resistance, the 199 genes were analyzed using the Ingenuity Pathway Analysis Tool. Fifty-one of these genes were mapped to genetic networks, and we validated the top-10 upregulated genes by real-time reverse transcriptase-polymerase chain reaction. Five novel genes, LUM, PDE3B, PDGF-C, NRG1 and PKD2, showed excellent concordance with the microarray data. In 48 patients with oral SCC (OSCC), positive immunohistochemical staining for the five genes correlated with chemoresistance to cisplatin-based combination chemotherapy. In addition, the expression of the five genes predicted the patient outcomes with chemotherapy. Furthermore, siRNA-directed suppressed expression of the five genes resulted in enhanced susceptibility to cisplatin-mediated apoptosis. These results suggested that these five novel genes have great potential for predicting the efficacy of cisplatin-based chemotherapy against OSCC. Global gene analysis of cisplatin-resistant cell lines may provide new insights into the mechanisms underlying clinical cisplatin resistance and improve the efficacy of chemotherapy for human HNSCC.
Yamano
Yukio
Y
Department of Clinical Molecular Biology, Chiba University, Japan.
Uzawa
Katsuhiro
K
Saito
Kengo
K
Nakashima
Dai
D
Kasamatsu
Atsushi
A
Koike
Hirofumi
H
Kouzu
Yukinao
Y
Shinozuka
Keiji
K
Nakatani
Ken
K
Negoro
Kenji
K
Fujita
Shigeyuki
S
Tanzawa
Hideki
H
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007632:Keratan Sulfate / Q000235:genetics / Q000378:metabolism; D000071234:Lumican; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D011508:Chondroitin Sulfate Proteoglycans; D002945:Cisplatin; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D007632:Keratan Sulfate; D000071234:Lumican; D008222:Lymphokines; D020890:Neuregulin-1; D010982:Platelet-Derived Growth Factor; D050396:TRPP Cation Channels; C000604306:LUM protein, human; C094131:NRG1 protein, human; C411423:platelet-derived growth factor C; C517291:PDE3B protein, human