Discovery of common SNPs in the miR-205/200 family-regulated epithelial to mesenchymal transition pathway and their association with risk for non-small cell lung cancer.

ABSTRACT The activation of the epithelial-to-mesenchymal transition (EMT) program is an important step for tumor initiation, invasion, and metastasis in solid tumors, including lung cancer. The purpose of this study was to identify the sequence variants in the miR-205/200 family-regulated EMT pathway and test their association with risk for lung cancer. Fifty samples were resequenced to identify sequence variants in the miR-205/200 family-regulated EMT pathway. The association between tagSNPs and risk for non-small cell lung cancer was discovered and validated in New Mexico (386 cases and 514 controls) and Massachusetts (2453 cases and 1555 controls) case-control studies, respectively. The function of SNPs on miR-200b-a-429 promoter activity was tested using luciferase reporter and expression assays. Forty-one sequence variants with minor allele frequency ≥ 0.03 were identified, and 16 variants were selected as tagSNPs. Genetic association analysis identified that the G allele of rs61768479 was associated with a 50% reduced risk for lung cancer (OR=0.50, 95%CI=0.30-0.85, uncorr-P=0.01); however, this association was not validated (OR=0.90, 95%CI=0.72-1.13, uncorr-P=0.35). The G allele of rs61768479 was associated with lower promoter activity and miR expression by disrupting the binding of NKX2.5. In summary, no association was identified between sequence variants in the miR-205/200 family-regulated EMT pathway and risk for lung cancer. However, this study identified a comprehensive panel of tagSNPs (n=16) in the miR-205/200 family-regulated EMT pathway that can be applied to other EMT-related phenotypes such as cancer chemoresistence and prognosis.

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    ABSTRACT: Rationale: Gene promoter methylation detected in sputum predicts lung cancer risk in smokers. Compared with non-Hispanic Whites (NHW), Hispanics have a lower age-standardized incidence for lung cancer. Objectives: This study compared the methylation prevalence in sputum of NHWs to Hispanics using the Lovelace Smokers cohort (n=1998) and evaluated the effect of Native American ancestry (NAA) and diet on biomarkers for lung cancer risk. Methods: Genetic ancestry was estimated using 48 ancestry markers. Diet was assessed by the Harvard University Dietary Assessment questionnaire. Methylation of 12 genes was measured in sputum using methylation-specific PCR. The association between NAA and risk for methylation was assessed using generalized estimating equations. The ethnic difference in the association between packyears and risk for lung cancer was assessed in the New Mexico lung cancer study. Measurements and Main Results: Overall Hispanics had a significantly increased risk for methylation across the 12 genes analyzed (OR = 1.18, P = 0.007). However, the risk was reduced by 32% (P = 0.032) in Hispanics with high versus low NAA. In the New Mexico lung cancer study, Hispanic non-small cell lung cancer cases have significantly lower packyears than NHW counterparts (P = 0.007). Furthermore, compared with NHW smokers, Hispanic smokers had a more rapidly increasing risk for lung cancer as a function of packyears (P = 0.058). Conclusions: NAA may be important risk modifiers for methylation in Hispanic smokers. Smoking intensity may have a greater impact on risk for lung cancer in Hispanics compared with NHWs.
    American Journal of Respiratory and Critical Care Medicine 09/2013; · 11.04 Impact Factor
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    ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are noncoding RNAs involved in posttranscriptional regulation of gene expression in cancer and provide new perspectives on the development of laryngeal squamous cell carcinoma (SCC). METHODS: miRNA expression of 6 pairs of laryngeal SCC and adjacent normal tissues was screened using miRNA array. Laser capture microdissection was applied to isolate a homogeneous group of cells from laryngeal SCC samples. The results of miRNA array analysis were validated in 48 pairs of laryngeal SCC and adjacent normal tissues using quantitative RT-PCR. RESULTS: Twenty-nine differentially expressed miRNAs were detected in the 6 pairs of laryngeal SCC, of which 6 were confirmed, including upregulation of miR-21, miR-93, miR-205, and miR-708 and downregulation of miR-125b and miR-145. Their putative target genes were predicted using 3 online software programs. CONCLUSION: These differentially expressed miRNAs may play a role in tumorigenesis and progression in laryngeal SCC and offer new angles for further investigations into the function of miRNAs. © 2012 Wiley Periodicals, Inc. Head Neck, 2012.
    Head & Neck 05/2012; · 2.83 Impact Factor
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    ABSTRACT: Polymorphisms in microRNAs (miRNAs) and their target sites (PolymiRTS) are known to disrupt miRNA function, leading to the development of disease and variation in physiological and behavioral phenotypes. Here, we describe recent updates to the PolymiRTS database (, an integrated platform for analyzing the functional impact of genetic polymorphisms in miRNA seed regions and miRNA target sites. Recent advances in genomic technologies have made it possible to identify miRNA-mRNA binding sites from direct mapping experiments such as CLASH (cross linking, ligation and sequencing of hybrids). We have integrated data from CLASH experiments in the PolymiRTS database to provide more complete and accurate miRNA-mRNA interactions. Other significant new features include (i) small insertions and deletions in miRNA seed regions and miRNA target sites, (ii) TargetScan context + score differences for assessing the impact of polymorphic miRNA-mRNA interactions and (iii) biological pathways. The browse and search pages of PolymiRTS allow users to explore the relations between the PolymiRTSs and gene expression traits, physiological and behavioral phenotypes, human diseases and biological pathways.
    Nucleic Acids Research 10/2013; · 8.81 Impact Factor


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