Intersex-like (IXL) is a cell survival regulator in pancreatic cancer with 19q13 amplification.
Pancreatic cancer is a highly aggressive disease characterized by poor prognosis and vast genetic instability. Recent microarray-based, genome-wide surveys have identified multiple recurrent copy number aberrations in pancreatic cancer; however, the target genes are, for the most part, unknown. Here, we characterized the 19q13 amplicon in pancreatic cancer to identify putative new drug targets. Copy number increases at 19q13 were quantitated in 16 pancreatic cancer cell lines and 31 primary tumors by fluorescence in situ hybridization. Cell line copy number data delineated a 1.1 Mb amplicon, the presence of which was also validated in 10% of primary pancreatic tumors. Comprehensive expression analysis by quantitative real-time reverse transcription-PCR indicated that seven transcripts within this region had consistently elevated expression levels in the amplified versus nonamplified cell lines. High-throughput loss-of-function screen by RNA interference was applied across the amplicon to identify genes whose down-regulation affected cell viability. This screen revealed five genes whose down-regulation led to significantly decreased cell viability in the amplified PANC-1 cells but not in the nonamplified MiaPaca-2 cells, suggesting the presence of multiple biologically interesting genes in this region. Of these, the transcriptional regulator intersex-like (IXL) was consistently overexpressed in amplified cells and had the most dramatic effect on cell viability. IXL silencing also resulted in G(0)-G(1) cell cycle arrest and increased apoptosis in PANC-1 cells. These findings implicate IXL as a novel amplification target gene in pancreatic cancer and suggest that IXL is required for cancer cell survival in 19q13-amplified tumors.
Kuuselo
Riina
R
Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.
Savinainen
Kimmo
K
Azorsa
David O
DO
Basu
Gargi D
GD
Karhu
Ritva
R
Tuzmen
Sukru
S
Mousses
Spyro
S
Kallioniemi
Anne
A
D017209:Apoptosis / Q000235:genetics*; D002470:Cell Survival; D022202:Chromosomes, Artificial, Bacterial; D002888:Chromosomes, Human, Pair 19; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D056892:Mediator Complex; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
C518742:MED29 protein, human; D056892:Mediator Complex; D014157:Transcription Factors