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The high expression of miR-31 in lung adenocarcinoma inhibits the malignancy of lung adenocarcinoma tumor stem cells.

ABSTRACT: Therapies for lung adenocarcinoma (LUAD) are mainly limited by drug resistance, metastasis or recurrence related to cancer stem cells (CSCs) with high proliferation and self-renewing. This research validated that miR-31 was over-expressed in LUAD by the analysis of generous clinical samples data. And the results of clinical data analysis showed that high expression of miR-31 was more common in patients with worse prognosis. The genes differentially expressed in LUAD tissues compared with normal tissues and A549CD133⁺ cells (LUAD CSCs) compared with A549 cells were separately screened from Gene Expression Profiling Interactive Analysis and GEO datasets. The target genes that may play a role in the regulation of lung adenocarcinoma was screened by comparison between the differential genes and the target genes of miR-31. The functional enrichment analysis of GO Biological Processes showed that the expression of target genes related to cell proliferation was increased, while the expression of target genes related to cell invasion and metastasis was decreased in LUAD tissues and A549CD133⁺ cells. The results suggested that miR-31 may have a significant inhibitory effect on the differentiation, invasion, metastasis and adhesion of LUAD CSCs, which was verified in vivo and in vitro experiments. Knock down of miR-31 accelerated xenograft tumor growth and liver metastasis in vivo. Likewise, the carcinogenicity, invasion and metastasis of A549CD133⁺ CSCs were promoted after miR-31 knockdown. The study validated that miR-31 was up regulated in LUAD and its expression may affect the survival time of patients with lung adenocarcinoma, which indicated that miR-31 may have potential value for diagnosis and prognosis of LUAD. However, the inhibitory effect of miR-31 on tumorigenesis, invasion and metastasis of lung adenocarcinoma CSCs suggested its complexity in the regulation of lung adenocarcinoma, which may be related to its extensive regulation of various target genes.

SUBMITTER: Xu R

PROVIDER: S-EPMC8408630 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The present study is to screen lymph node metastasis-related microRNAs (miRNAs) in lung adenocarcinoma (LUAD) and uncover their underlying mechanisms.Methods: The miRNA microarray dataset was collected from the Gene Expression Omnibus database under accession number GSE64859. The differentially expressed miRNAs (DEMs) were identified using a t-test. Target genes of DEMs were predicted through the miRWalk2.0 database. The function of these target genes was annotated with the clusterProfiler and the Database for Annotation, Visualization and Integrated Discovery (DAVID) tools. Protein-protein interaction network was established using the STRING database to extract hub target genes. The expressions and associations with survival and lymph node metastasis of miRNAs and target genes were validated by analysis of The Cancer Genome Atlas (TCGA) dataset.Results: Eight DEMs were identified between lymph node metastasis and non-metastasis samples of GSE64859 dataset. miRNA-target gene pairs were predicted between six DEMs and 251 target genes (i.e. hsa-miR-224-PRPF4B, hsa-miR-147b-WDR82 and hsa-miR-31-NR3C2). The clusterProfiler analysis showed WDR82 was involved in the mRNA surveillance pathway, while the GO enrichment analysis using the DAVID database indicated PRPF4B participated in the protein phosphorylation and NR3C2 was related with the transcription, DNA-templated. WDR82 and PRPF4B may be hub genes because they could interact with others. Two DEMs (miR-31-5p and miR-31-3p) and 45 target genes (including PRPF4B and NR3C2) were significantly associated with overall survival. The expressions of miR-224 and miR-147b were validated to be upregulated, while WDR82, PRPF4B and NR3C2 were downregulated in lymph node metastasis samples of TCGA datasets compared with non-metastasis samples. Also, there were significantly negative expression correlations between miR-147b and WDR82, between miR-224 and PRPF4B, as well as between miR-31 and NR3C2 in LUAD samples.Conclusions: The present study identified several crucial miRNA-mRNA interaction pairs, which may provide novel explanations for the lymph node metastasis and poor prognosis for LUAD patients.

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The high expression of miR-31 in lung adenocarcinoma inhibits the malignancy of lung adenocarcinoma tumor stem cells.

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