Abstract
Through a new hypothesis-driven and microRNA-pathway-based SNP (miR-SNP) association study we identified a novel miR-SNP (rs713065) in the 3′UTR region of FZD4 gene linked with decreased risk of death in early stage NSCLC patients. We determined biological function and mechanism of action of this FZD4-miR-SNP biomarker in a cellular platform. Our data suggest that FZD4-miR-SNP loci may significantly influence overall survival in NSCLC patients by specifically interacting with miR-204 and modulating FZD4 expression and cellular function in the Wnt-signaling-driven tumor progression. Our findings are bridging the gap between the discovery of epidemiological SNP biomarkers and their biological function and will enable us to develop novel therapeutic strategies that specifically target epigenetic markers in the oncogenic Wnt/FZD signaling pathways in NSCLC.
Highlights
Single nucleotide polymorphisms (SNPs) in miRNA genes and miRNA-associated pathways have significant effects on gene expression and cellular processes by disrupting miRNA biogenesis and modulating miRNA-messenger RNAs (mRNAs) target interactions
There was a significant decrease in GFP expression in H1299 cells transfected with SNP-3′ untranslated regions (3′UTRs) compared with those transfected with WT-3′UTR after 1, 2, and 3 hours (h)
We detected that GFP expression was significantly decreased in cells from H1299, H226, A549, H661, and H1975 lung cancer cell lines transfected with GFP-SNP-3′UTR compared with cells that were transfected with GFP-WT3′UTR (Fig. 1B)
Summary
Single nucleotide polymorphisms (SNPs) in miRNA genes and miRNA-associated pathways (miR-SNPs) have significant effects on gene expression and cellular processes by disrupting miRNA biogenesis and modulating miRNA-mRNA target interactions. SNPs in miRNA regulatory pathways (miR-SNPs) that could be included in three categories of genes: miRNA genes, miRNA biogenesis genes, and miRNA target genes, can affect the transcription and processing precursor miRNA (pre-miRNA), modulate the affinity of miRNA-mRNA binding, abolish an existing binding site, or create abnormal binding sites These inherited genetic miR-SNP variants in miRNA binding sites within the 3′UTRs of target genes can significantly contribute to cancer risk and outcomes by regulating target gene expression and/or function[15, 16]. We intend to identify endogenous miRNAs that are interacting with Wnt-miR-SNPs and to determine how these Wnt-SNP- associated miRNAs differentially regulate their host/target gene expression and cellular function in NSCLC cells in vitro and in vivo. We will focus on to functionally characterize and validate the C allele of FZD4-miR-SNP, rs713065, in the miR-204 binding site in the FZD4 3′UTR, which was shown to be associated with a less aggressive NSCLC phenotype[30] and to determine the biological and clinical relevance of this novel epidemiological FZD4-miR-SNP biomarker in NSCLC cell lines, preclinical mouse models, and in clinical plasma and tissue samples
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