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Serum MiR-4687-3p Has Potential for Diagnosis and Carcinogenesis in Non-small Cell Lung Cancer.

ABSTRACT: The lack of a useful biomarker partly contributes to the increased mortality of non-small cell lung cancer (NSCLC). MiRNAs have become increasingly appreciated in diagnosis of NSCLC. In the present study, we used microarray to screen 2,549 miRNAs in serum samples from the training cohort (NSCLC, n = 10; the healthy, n = 10) to discover differentially expressed miRNAs (DEMs). Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was applied to validate the expression level of selected overexpressed DEMs of NSCLC in a validation cohort (NSCLC, n = 30; the healthy, n = 30). Area under the receiver operating characteristic curve (AUC) was performed to evaluate diagnostic capability of the DEMs. The expression of the miRNAs in tissues was analyzed based on the TCGA database. Subsequently, the target genes of the miR-4687-3p were predicted by TargetScan. Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were tested by R software (ClusterProfiler package). NSCLC cells were transfected with inhibitor or mimic to down-regulate or up-regulate the miR-4687-3p level. The function of miR-4687-3p on proliferation, invasion, and migration of lung cancer cells were investigated through CCK-8 and Transwell assays, respectively. In the results, we identified serum miR-4687-3p that provided a high diagnostic accuracy of NSCLC (AUC = 0.679, 95%CI: 0.543-0.815) in the validation cohort. According to the TCGA database, we found that the miR-4687-3p level was significantly higher in NSCLC tissues than in normal lung tissues (p < 0.05). GO and KEGG pathway enrichment analysis showed that postsynaptic specialization and TGF-? signaling pathway were significantly enriched. Down-regulation of miR-4687-3p could suppress the proliferation, invasion, and migration of the NSCLC cells, compared with inhibitor negative control (NC). Meanwhile, overexpression of miR-4687-3p could promote the proliferation, invasion, and migration of the NSCLC cells compared with mimic NC. As a conclusion, our study first discovered that serum miR-4687-3p might have clinical potential as a non-invasive diagnostic biomarker for NSCLC and play an important role in the development of NSCLC.

SUBMITTER: Liu M

PROVIDER: S-EPMC7721467 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Serum MiR-4687-3p Has Potential for Diagnosis and Carcinogenesis in Non-small Cell Lung Cancer.

Liu Man M Si Qiufang Q Ouyang Songyun S Zhou Zhigang Z Wang Meng M Zhao Chunling C Yang Ting T Wang Yulin Y Zhang Xue X Xie Wenbo W Dai Liping L Li Jitian J

Frontiers in genetics 20201123

The lack of a useful biomarker partly contributes to the increased mortality of non-small cell lung cancer (NSCLC). MiRNAs have become increasingly appreciated in diagnosis of NSCLC. In the present study, we used microarray to screen 2,549 miRNAs in serum samples from the training cohort (NSCLC, <i>n</i> = 10; the healthy, <i>n</i> = 10) to discover differentially expressed miRNAs (DEMs). Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was applied to validate the exp ...[more]

PMID: 33329742

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Project description:Background:Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers. Serum microRNAs (miRNAs), due to their high stability, have the potential to become valuable noninvasive biomarkers. This present study was aimed to identify the serum miRNAs expression signatures for the diagnosis and prognosis of NSCLC using bioinformatics analysis. Methods:A total of 12 miRNAs profiling studies have been identified in Pubmed, Gene Expression Omnibus (GEO), and ArreyExpress databases. Differentially expressed miRNAs (DEmiRNAs) were analyzed according to GEO2R online tool and RRA method from R. Then, prediction of DEmiRNAs' target genes from TargetScan, PicTar, miRDB, Tarbase, and miRanda database. Furthermore, we using reverse transcription- quantitative polymerase chain reaction (RT-qPCR) to evaluate the expression levels of DEmiRNAs in serum samples obtained from NSCLC patients and healthy controls. Subsequently, the clinical significance of the tested miRNAs was determined using receiver operating characteristic (ROC) analysis and Cox regression analysis. Results:A total of 27 DEmiRNAs were identified and 5 of them (miR-1228-3p, miR-1228-5p, miR-133a-3p, miR-1273f, miR-545-3p) were significantly up-regulated and 4 of them (miR-181a-5p, miR-266-5p, miR-361-5p, miR-130a-3p) were significantly down-regulated in NSCLC patients compared with healthy controls. RT-qPCR validated that miR-1228-3p (P?=0.006) and miR-181a-5p (P?=0.030) were significantly differentially expressed in the serum of NSCLC patients and healthy controls. ROC analysis on miR-1228-3p and miR-181a-5p revealed the area under the curve (AUC) of 0.685 (95% confidence interval [CI], 0.563-0.806; P?=0.006) and 0.647 (95% CI, 0.506-0.758; P?=0.049). ROC analysis on miR-1228-3p combined miR-181a-5p revealed the AUC of 0.711 (95% CI, 0.593-0.828; P?=0.002). Multivariate Cox regression analysis demonstrated that the high serum miR-1228-3p level was an independent factor for the poor prognosis of NSCLC patients. Conclusions:Serum miR-1228-3p and miR-181a-5p are potential noninvasive biomarkers for the diagnosis and prognosis of NSCLC patients.

Project description:BackgroundFerroptosis is a newly generated regulatory cell death promoted by the accumulated lipid-based reactive oxygen species (ROS). Solute carrier family 7 member 11 (SLC7A11), the cystine/glutamate antiporter, is known as a ferroptosis executor that exhibits a positive correlation with carcinoma progression because of antioxidant function. Nonetheless, it is yet unclear on the understanding of ferroptosis regulation in lung cancer.MethodsDatabase, qRT-PCR, Western-blot (WB), and immunohistochemistry were utilized to determine SLC7A11 expression and function, as well as gene iron related to necrosis in clinical tissue specimens and cells; a ferroptosis inducer, inhibitors, and SLC7A11 lentivirus were used to confirm SLC7A11's biological activity in cell viability, oxidative stress, lipid peroxidation, and iron ion enrichment in non-small cell lung cancer (NSCLC) in different cells; lentivirus was used to infect lung adenocarcinoma cell lines to acquire miR-27a-3p overexpression and knockdown cell lines, and to detect SLC7A11 level through qRT-PCR and WB. The influence of upregulated/downregulated miR-27a-3p on ferroptosis and other related biological characteristics of lung adenocarcinoma cell lines was detected.ResultsUpregulated SLC7A11 was shown in NSCLC patients and cells, and increased SLC7A11 had a relation to the poorly prognostic status of NSCLC patients. Besides, a novel miRNA, miR-27a-3p, was an essential modulator of ferroptosis via directly targeting SLC7A11 in NSCLC cells. Overexpressing miR-27a-3p led to SLC7A11 suppression via directly binding to its 3'-UTR, followed by the reduction of erastin-caused ferroptosis. In contrast, inhibited miR-27a-3p resulted in an increase in NSCLC cells' sensitivity to erastin. Of importance, the accumulated lipid ROS and cell death of iron peptide mediated by anti-miR-27a-3p can be eliminated by impeding the glutamylation process. Our literature collectively uncovered that miR-27a-3p modulated ferroptosis by targeting SLC7A11 in NSCLC cells, illustrating the important role of miRNA in ferroptosis.ConclusionMiR-27a-3p modulates ferroptosis via targeting SLC7A11 in NSCLC cells, implying the significant role of miR-27a-3p/SLC7A11 in ferroptosis.

Dataset Information

Serum MiR-4687-3p Has Potential for Diagnosis and Carcinogenesis in Non-small Cell Lung Cancer.

Publications

Serum MiR-4687-3p Has Potential for Diagnosis and Carcinogenesis in Non-small Cell Lung Cancer.

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