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Genetic variants in microRNAs predict non-small cell lung cancer prognosis in Chinese female population in a prospective cohort study.

ABSTRACT: To investigate the prognostic effect of microRNA single nucleotide polymorphisms (SNP) on non-small cell lung cancer (NSCLC) patients, 658 female participants from northeast China were enrolled in our prospective cohort study and followed up from 2010 to 2015. C-containing genotypes of miR-149 rs2292832 were associated with better overall survival (OS). The joint effect of miR-149 and miR-196a2 and the joint effect of miR-149 and miR-608 were also observed in our study. To verify the function of miR-149 rs2292832, A549 cell lines were stably transfected with lenti-virus containing miR-149-C vector, miR-149-T vector and empty vector. Cells containing C allele assumed a higher expression level of miR-149, a decrease in cell growth and the sensitivity to anticancer drug when compared with cells containing T allele. The role of miR-149 playing in cancer prognosis may function through DNA topoisomerases 1 (TOP1) pathway, according to the results from luciferase reporter assays. In conclusion, miR-149 C allele may be a prognostic biomarker for better NSCLC OS.

SUBMITTER: Lingzi X

PROVIDER: S-EPMC5347756 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Genetic variants in microRNAs predict non-small cell lung cancer prognosis in Chinese female population in a prospective cohort study.

Lingzi Xia X Zhihua Yin Y Xuelian Li L Yangwu Ren R Haibo Zhang Z Yuxia Zhao Z Baosen Zhou Z

Oncotarget 20161201 50

To investigate the prognostic effect of microRNA single nucleotide polymorphisms (SNP) on non-small cell lung cancer (NSCLC) patients, 658 female participants from northeast China were enrolled in our prospective cohort study and followed up from 2010 to 2015. C-containing genotypes of miR-149 rs2292832 were associated with better overall survival (OS). The joint effect of miR-149 and miR-196a2 and the joint effect of miR-149 and miR-608 were also observed in our study. To verify the function of ...[more]

PMID: 27825117

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Project description:BackgroundLung cancer is the leading cause of cancer morbidity and mortality worldwide, however, the individualized treatment is still unsatisfactory. DNA methylation can affect gene regulation and may be one of the most valuable biomarkers in predicting the prognosis of lung adenocarcinoma. This study was aimed to identify methylation CpG sites that may be used to predict lung adenocarcinoma prognosis.MethodsThe Cancer Genome Atlas (TCGA) database was used to detect methylation CpG sites associated with lung adenocarcinoma prognosis and construct a methylation signature model. Then, a Chinese cohort was carried out to estimate the association between methylation and lung adenocarcinoma prognosis. Biological function studies, including demethylation treatment, cell proliferative capacity, and gene expression changes in lung adenocarcinoma cell lines, were further performed.ResultsIn the TCGA set, three methylation CpG sites were selected that were associated with lung adenocarcinoma prognosis (cg14517217, cg15386964, and cg18878992). The risk of mortality was increased in lung adenocarcinoma patients with the gradual increase level of methylation signature based on three methylation sites levels (HR = 45.30, 95% CI = 26.69-66.83; p < 0.001). The C-statistic value increased to 0.77 when age, gender, and other clinical variables were added to the signature to prediction model. A similar situation was confirmed in Chinese lung adenocarcinoma cohort. In the biological function studies, the proliferative capacity of cell lines was inhibited when the cells were demethylated with 5-aza-2'-deoxycytidine (5-aza-2dC). The mRNA and protein expression levels of SEPT9 and HIST1H2BH (cg14517217 and cg15386964) were downregulated with different concentrations of 5-aza-2dC treatment, while cg18878992 showed the opposite result.ConclusionThis study is the first to develop a three-CpG-based model for lung adenocarcinoma, which is a practical and useful tool for prognostic prediction that has been validated in a Chinese population.

Project description:BackgroundEarly-stage female lung adenocarcinoma is the most common type of lung cancer encountered in thoracic surgery departments. Tumor-node-metastasis (TNM) staging does not adequately explain a significant stratification phenomenon in the prognosis of patients with stage I lung adenocarcinoma. We aimed to investigate the contributory role of miR-940 in the prognosis prediction.MethodsWe analyzed the microRNA (miRNA) expression level in tumor tissues (high-risk group vs. low-risk group) from 12 non-smoking female patients with stage I lung adenocarcinoma using miRNA array. Bioinformatic analyses of miR-940 were also carried out based on the public database. Then, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) tests of the tissue samples were further validated. And miR-940's function was analyzed and potential target genes were predicted.ResultsIn all, 24 miRNAs were found to be significantly different between the high-risk group and low-risk group. The expression level of miR-940 was lower in tumor tissue (P=0.011), and the survival rate in the high miR-940 group was higher [hazard ratio (HR) =0.688; P=0.011]. Gene Ontology (GO) analysis showed that the assembly functions of targets regulated by miR-940 were mainly enriched in regulation of myeloid cell differentiation, G1/S transition of mitotic cell cycle, and cellular response to environmental stimulus. miR-940 is involved in transforming growth factor-beta (TGF-beta) signaling pathway; TNF signaling pathway; and estrogen signaling pathway. The number of lung adenocarcinoma cells (A549) was significantly decreased after miR-940 was transfected. Ten epithelial-to-mesenchymal-transition (EMT)-associated genes (MMP9, ZEB1, CDH1, KRT8, KRT18 KET19, TWIST1, VIM, SNAI1, and SNAI2) were found to be significantly related to miR-940.ConclusionsThe present study showed that miR-940 might be a protective factor for positive prognosis in early stage nonsmoking female lung adenocarcinoma, with transforming growth factor-beta (TGF-beta) pathway, TNF pathway, and matrix metalloprotein (MMP9) being potential targets.

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Genetic variants in microRNAs predict non-small cell lung cancer prognosis in Chinese female population in a prospective cohort study.

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Genetic variants in microRNAs predict non-small cell lung cancer prognosis in Chinese female population in a prospective cohort study.

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