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MiR-92b-3p Functions As A Key Gene In Esophageal Squamous Cell Cancer As Determined By Co-Expression Analysis.

ABSTRACT: Background:Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy. The aims of the present study were to screen the critical miRNA and corresponding target genes that related to development of ESCC by weighted gene correlation network analysis (WGCNA) and investigate the functions by experimental validation. Methods:Datasets of mRNA and miRNA expression data were downloaded from GEO. The R software was used for data preprocessing and differential expression gene analysis. The differentially expressed protein-coding genes (DEGs) and miRNAs (DEMs) were selected (FDR <0.05 or |Fold Change (FC)| >1.5). Meanwhile, 81 expression data of ESCC patients in TCGA combined with clinic information were applied by WGCNA to create networks. The correlational analyses between each module and clinical parameters were conducted, and enrichment analyses of GO and KEGG were subsequently performed. Then, a series of experiments were conducted in ESCC cells by use of miRNA mimics. Results:In total, 4,023 DEGs and 328 DEMs were screened. After checking good genes and samples, 3,841 genes (3,696 DEGs and 145 DEMs) were used for WGCNA. As a consequence, altogether 11 gene modules were found. Among them, the brown modules were found to be strongly inversely associated with pathological grade. Meanwhile, has-mir-92b, the only miRNA in brown module, had a positive correlation with grade and negatively correlated with potential target gene (KFL4 and DCS2) in the same module. Furthermore, an increased expression of miR-92b-3p and down-regulated KLF4 and DSC2 protein was detected in the ESCC clinical samples. Up-regulated miR-92b-3p shortened G0/G1 phase and promote ESCC cells invasion and migration. Furthermore, we verified that DSC2 and KFL4 was target genes of miR-92b-3p by luciferase report assay. Conclusion:WGCNA is an efficient approach to system biology. By this procedure, miR-92b-3p was identified as an ESCC-promoting gene by target KLF4 and DCS2.

SUBMITTER: Wang W

PROVIDER: S-EPMC6799829 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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miR-92b-3p Functions As A Key Gene In Esophageal Squamous Cell Cancer As Determined By Co-Expression Analysis.

Wang Wanpeng W Fu Sengwang S Lin Xiaolu X Zheng Jinhui J Pu Juan J Gu Yun Y Deng Weijun W Liu Yanyan Y He Zhongxiang Z Liang Wei W Wang Chengshi C

OncoTargets and therapy 20191014

<h4>Background</h4>Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy. The aims of the present study were to screen the critical miRNA and corresponding target genes that related to development of ESCC by weighted gene correlation network analysis (WGCNA) and investigate the functions by experimental validation.<h4>Methods</h4>Datasets of mRNA and miRNA expression data were downloaded from GEO. The R software was used for data preprocessing and differential expression ge ...[more]

PMID: 31686859

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Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most prevalent gastrointestinal malignancies with high mortality. Circular RNAs (CircRNAs) have become a research hotspot in recent years for their vital roles in cancer development and progression. This study aims to clarify the roles of circNTRK2 and its underlying molecular mechanisms in ESCC.MethodsThe levels of circNTRK2, miR-140-3p, and nuclear receptor-interacting protein 1 (NRIP1) mRNA were examined by qRT-PCR. The cell proliferation ability was detected via CCK-8, EdU and colony formation assays. The invasion capacity was tested by using transwell assay. The apoptotic rate was evaluated through flow cytometry. The protein levels of cleaved PARP, cleaved caspase-3, E-cadherin, vimentin, and NRIP1 were measured by western blot assay. The validation of circular structure was performed by Sanger sequencing, divergent primer PCR, and RNase R treatments. The ceRNA regulatory mechanism of circNTRK2 was observed via dual-luciferase reporter, RIP and RNA pull-down assays. The mice xenograft models were constructed to confirm the oncogenicity of circNTRK2 in ESCC in vivo.ResultsCircNTRK2 was highly expressed in ESCC tissues and cells. High expression of circNTRK2 was correlated with advanced TNM stage, lymph node metastasis and short survival. Knockdown of circNTRK2 inhibited ESCC cell proliferation, invasion and epithelial-mesenchymal transition (EMT), and accelerated apoptosis in vitro. Mechanistic assays disclosed that circNTRK2 could act as a sponge for miR-140-3p to abate its suppression on target NRIP1 expression. Moreover, miR-140-3p-induced inhibitory effects on ESCC cell malignant phenotypes were attenuated by the overexpression of circNTRK2. In addition, depletion of NRIP1 impeded cell proliferation, invasion and EMT, while enhanced apoptosis. Furthermore, silencing of circNTRK2 suppressed cell proliferation and invasion through regulating NRIP1 expression. Also, knockdown of circNTRK2 slowed ESCC tumor growth in vivo.ConclusionCircNTRK2 promoted ESCC progression by regulating miR-140-3p/NRIP1 pathway. Our findings contribute to a better understanding of circRNAs as miRNA sponges and highlight a promising therapy target in ESCC.

Project description:BackgroundMicroRNAs have an important role in diverse biological processes including tumorigenesis. MiR-223 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in lung squamous cell carcinoma (LSCC). The following study investigates the role of miR-223-3p in LSCC growth and metastasis and its underlying mechanism.MethodsMicroRNA profiling analyses were conducted to determine differential miRNAs expression levels in LSCC tumor tissues that successfully formed xenografts in immunocompromised mice (XG) and failed tumor tissues (no-XG). RT-PCR and in situ hybridization (ISH) was performed to evaluate the expression of miR-223-3p in 12 paired adjacent normal tissues and LSCC specimens. Cell proliferation and migration were assessed by CCK-8, colony formation and Transwell assay, respectively. The role of miR-223-3p in LSCC tumorigenesis was examined using xenograft nude models. Bioinformatics analysis, Dual-luciferase reporter assays, Chromatin immunoprecipitation (ChIP) assay and Western blot analysis were used to identify the direct target of miR-223-3p and its interactions.ResultsMiR-223-3p was downregulated in LSCC tissues that successfully formed xenografts (XG) compared with tumor tissues that failed (no-XG), which was also significantly reduced in LSCC tissues compared with the adjacent normal tissues. Gain- and loss-of function experiments showed that miR-223-3p inhibited proliferation and migration in vitro. More importantly, miR-223-3p overexpression greatly suppressed tumor growth in vivo. Mechanistically, we found that mutant p53 bound to the promoter region of miR-223 and reduced its transcription. Meanwhile, p53 is a direct target of miR-223-3p. Thus, miR-223-3p regulated mutant p53 expression in a feedback loop that inhibited cell proliferation and migration.ConclusionsOur study identified miR-223-3p, as a tumor suppressor gene, markedly inhibited cell proliferation and migration via miR-223-3p-mutant p53 feedback loop, which suggested miR-223-3p might be a new therapeutic target in LSCC bearing p53 mutations.

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MiR-92b-3p Functions As A Key Gene In Esophageal Squamous Cell Cancer As Determined By Co-Expression Analysis.

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miR-92b-3p Functions As A Key Gene In Esophageal Squamous Cell Cancer As Determined By Co-Expression Analysis.

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