title: Identification of a functional SNP in the 3'UTR of CXCR2 that is associated with reduced risk of lung cancer.
abstract: Global changes in gene expression accompany the development of cancer. Thus, inherited variants in miRNA-binding sites are likely candidates for conferring inherited susceptibility. Using an in silico approach, we compiled a comprehensive list of SNPs predicted to modulate miRNA binding in genes from several key lung cancer pathways. We then investigated whether these SNPs were associated with lung cancer risk in two independent populations. In general, SNPs in miRNA-binding sites are rare. However, some allelic variation was observed. We found that rs1126579 in CXCR2 was associated with a reduced risk of lung cancer in both European American [ORTT vs. CC 0.56 (0.37-0.88); P = 0.008] and Japanese [ORTT vs. CC 0.62 (0.38-1.00); P = 0.049] populations. Furthermore, we found that the SNP disrupted a novel binding site for miR-516a-3p, led to a moderate increase in CXCR2 mRNA and protein expression, and increased MAPK signaling. Moreover, analysis of rs1126579 with serum levels of IL8, its endogenous ligand, supported an interaction whereby rs1126579-T and high serum IL8 conferred synergistic protection from lung cancer. Our findings demonstrate a function for a 3'UTR SNP in modulating CXCR2 expression, signaling, and susceptibility to lung cancer.
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Bríd M
authors.initials: BM
authors.lastname: Ryan
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Robles
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Department of Pathology, Stanford University Hospital and Clinics, Stanford, California.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McClary
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Majda
authors.initials: M
authors.lastname: Haznadar
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Elise D
authors.initials: ED
authors.lastname: Bowman
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Pine
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Derek
authors.initials: D
authors.lastname: Brown
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Khan
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Kouya
authors.initials: K
authors.lastname: Shiraishi
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Okayama
authors.affiliation: BioServe Ltd., Beltsville, Maryland.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Modali
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Curtis_Harris@nih.gov.
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D000483:Alleles; D001665:Binding Sites; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007564:Japan; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D023063:Receptors, Interleukin-8B / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; D016209:Interleukin-8; D008024:Ligands; D035683:MicroRNAs; D023063:Receptors, Interleukin-8B