title: CD44-SLC1A2 gene fusions in gastric cancer.
abstract: Fusion genes are chimeric genes formed in cancers through genomic aberrations such as translocations, amplifications, and rearrangements. To identify fusion genes in gastric cancer, we analyzed regions of chromosomal imbalance in a cohort of 106 primary gastric cancers and 27 cell lines derived from gastric cancers. Multiple samples exhibited genomic breakpoints in the 5' region of SLC1A2/EAAT2, a gene encoding a glutamate transporter. Analysis of a breakpoint-positive SNU16 cell line revealed expression of a CD44-SLC1A2 fusion transcript caused by a paracentric chromosomal inversion, which was predicted to produce a truncated but functional SLC1A2 protein. In primary tumors, CD44-SLC1A2 gene fusions were detected in 1 to 2% of gastric cancers, but not in adjacent matched normal gastric tissues. When we specifically silenced CD44-SLC1A2, cellular proliferation, invasion, and anchorage-independent growth were significantly reduced. Conversely, CD44-SLC1A2 overexpression in gastric cells stimulated these pro-oncogenic traits. CD44-SLC1A2 silencing caused significant reductions in intracellular glutamate concentrations and sensitized SNU16 cells to cisplatin, a commonly used chemotherapeutic agent in gastric cancer. We conclude that fusion of the SLC1A2 gene coding region to CD44 regulatory elements likely causes SLC1A2 transcriptional dysregulation, because tumors expressing high SLC1A2 levels also tended to be CD44-SLC1A2-positive. CD44-SLC1A2 may represent a class of gene fusions in cancers that establish a pro-oncogenic metabolic milieu favoring tumor growth and survival.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
authors.forename: Jiong
authors.initials: J
authors.lastname: Tao
authors.forename: Nian Tao
authors.initials: NT
authors.lastname: Deng
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ramnarayanan
authors.forename: Baohua
authors.initials: B
authors.lastname: Huang
authors.forename: Hue Kian
authors.initials: HK
authors.lastname: Oh
authors.forename: Siew Hong
authors.initials: SH
authors.lastname: Leong
authors.forename: Seong Soo
authors.initials: SS
authors.lastname: Lim
authors.forename: Iain Beehuat
authors.initials: IB
authors.lastname: Tan
authors.forename: Chia Huey
authors.initials: CH
authors.lastname: Ooi
authors.forename: Jeanie
authors.initials: J
authors.lastname: Wu
authors.forename: Minghui
authors.initials: M
authors.lastname: Lee
authors.forename: Shenli
authors.initials: S
authors.lastname: Zhang
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
authors.forename: Duane T
authors.initials: DT
authors.lastname: Smoot
authors.forename: Hassan
authors.initials: H
authors.lastname: Ashktorab
authors.forename: Oi Lian
authors.initials: OL
authors.lastname: Kon
authors.forename: Valere
authors.initials: V
authors.lastname: Cacheux
authors.forename: Celestial
authors.initials: C
authors.lastname: Yap
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D027342:Excitatory Amino Acid Transporter 2; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion / Q000235:genetics*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D018960:Hyaluronan Receptors; D011993:Recombinant Fusion Proteins; C493397:SLC1A2 protein, human