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00085472can142101-sup-134840_1_supp_2702323_ndgfg1.ppt (3.68 MB)

Supplementary Figure 2 from Identification of a Functional SNP in the 3′UTR of CXCR2 That Is Associated with Reduced Risk of Lung Cancer

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posted on 2023-03-30, 23:27 authored by Bríd M. Ryan, Ana I. Robles, Andrew C. McClary, Majda Haznadar, Elise D. Bowman, Sharon R. Pine, Derek Brown, Mohammed Khan, Kouya Shiraishi, Takashi Kohno, Hirokazu Okayama, Ramakrishna Modali, Jun Yokota, Curtis C. Harris

Representative images of CXCR2 staining in lung cancer specimens from the NCI-MD case control study.

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ARTICLE 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. Cancer Res; 75(3); 566–75. ©2014 AACR.

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