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MiR-491-5p inhibits the proliferation and migration of A549 cells by FOXP4.

ABSTRACT: Aberrant expression of microRNAs (miRNAs/miRs) plays a key role in the development of non-small cell lung cancer (NSCLC). In the present study, lower miRNA (miR)-491-5p levels and a higher forkhead box P4 (FOXP4) mRNA level were observed in NSCLC tissues and cell lines, compared to adjacent tissues and the normal human lung epithelial cell line BEAS-2B, respectively. A549 cell proliferation and migration were inhibited upon transfection of miR-491-5p mimics compared to miR-negative control (NC) mimics. In addition, compared to miR-NC mimics, overexpression of miR-491-5p decreased FOXP4 expression, while downregulation of miR-491-5p increased FOXP4 expression in A549 cells. The dual luciferase assay confirmed that the 3'untranslated region of FOXP4 was a target for miR-491-5p in A549 cells. Moreover, compared with the control short hairpin (sh)RNA, there was lower expression levels of TGF-β and its downstream targets (MMP-2 and MMP-9) in the FOXP4 shRNA group. Similarly, compared to miR-NC mimics, overexpression of miR-491-5p decreased MMP-2 and MMP-9 expression levels. In FOXP4-knockdown A549 cells, overexpression of miR-491-5p showed little effect on cell proliferation/migration. In A549 cells, overexpression of FOXP4 partially reversed the miR-491-5p mimics-induced inhibition on the cell proliferation and migration. These results may provide new insights into the role of miR-491-5p in NSCLC.

SUBMITTER: Wu F

PROVIDER: S-EPMC8082662 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Astrocytomas are common malignant intracranial tumors that comprise the majority of adult primary central nervous system tumors. MicroRNAs (miRNAs) are small, non-coding RNAs (20-24 nucleotides) that post-transcriptionally modulate gene expression by negatively regulating the stability or translational efficiency of their target mRNAs. In our previous studies, we found that the downregulation of miR-106a-5p in astrocytomas is associated with poor prognosis. However, its specific gene target(s) and underlying functional mechanism(s) in astrocytomas remain unclear. In this study, we used mRNA microarray experiments to measure global mRNA expression in the presence of increased or decreased miR-106a-5p levels. We then performed bioinformatics analysis based on multiple target prediction algorithms to obtain candidate target genes that were further validated by computational predictions, western blot analysis, quantitative real-time PCR, and the luciferase reporter assay. Fas-activated serine/threonine kinase (FASTK) was identified as a direct target of miR-106a-5p. In human astrocytomas, miR-106a-5p is downregulated and negatively associated with clinical staging, whereas FASTK is upregulated and positively associated with advanced clinical stages, at both the protein and mRNA levels. Furthermore, Kaplan-Meier analysis revealed that the reduced expression of miR-106a-5p or the increased expression of FASTK is significantly associated with poor survival outcome. These results further supported the finding that FASTK is a direct target gene of miR-106a-5p. Next, we explored the function of miR-106a-5p and FASTK during astrocytoma progression. Through gain-of-function and loss-of-function studies, we demonstrated that miR-106a-5p can significantly inhibit cell proliferation and migration and can promote cell apoptosis in vitro. The knockdown of FASTK induced similar effects on astrocytoma cells as those induced by the overexpression of miR-106a-5p. These observations suggest that miR-106a-5p functions as a tumor suppressor during the development of astrocytomas by targeting FASTK.

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MiR-491-5p inhibits the proliferation and migration of A549 cells by FOXP4.

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