Integrative genomics identifies RAB23 as an invasion mediator gene in diffuse-type gastric cancer.
Recurrent genomic amplifications and deletions are frequently observed in primary gastric cancers (GC). However, identifying specific oncogenes and tumor suppressor genes within these regions can be challenging, as they often cover tens to hundreds of genes. Here, we combined high-resolution array-based comparative genomic hybridization (aCGH) with gene expression profiling to target genes within focal high-level amplifications in GC cell lines, and identified RAB23 as an amplified and overexpressed Chr 6p11p12 gene in Hs746T cells. High RAB23 protein expression was also observed in some lines lacking RAB23 amplification, suggesting additional mechanisms for up-regulating RAB23 besides gene amplification. siRNA silencing of RAB23 significantly reduced cellular invasion and migration in Hs746T cells, whereas overexpression of RAB23 enhanced cellular invasion in AGS cells. RAB23 amplifications in primary gastric tumors were confirmed by both fluorescence in situ hybridization and genomic qPCR, and in two independent patient cohorts from Hong Kong and the United Kingdom RAB23 expression was significantly associated with diffuse-type GC (dGC) compared with intestinal-type GC (iGC). These results provide further evidence that dGC and iGC likely represent two molecularly distinct tumor types, and show that investigating focal chromosomal amplifications by combining high-resolution aCGH with expression profiling is a powerful strategy for identifying novel cancer genes in regions of recurrent chromosomal aberration.
Hou
Qingsong
Q
National Cancer Centre, Department of Biochemistry, National University of Singapore, Duke-NUS Graduate Medical School, and Genome Institute of Singapore, Singapore, Singapore.
Wu
Yong Hui
YH
Grabsch
Heike
H
Zhu
Yansong
Y
Leong
Siew Hong
SH
Ganesan
Kumaresan
K
Cross
Debra
D
Tan
Lay Keng
LK
Tao
Jiong
J
Gopalakrishnan
Veena
V
Tang
Bor Luen
BL
Kon
Oi Lian
OL
Tan
Patrick
P
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002465:Cell Movement; D002874:Chromosome Mapping; D022202:Chromosomes, Artificial, Bacterial; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D020691:rab GTP-Binding Proteins / Q000235:genetics*
D012333:RNA, Messenger; D034741:RNA, Small Interfering; C486614:RAB23 protein, human; D020691:rab GTP-Binding Proteins