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MLK3 is a newly identified microRNA-520b target that regulates liver cancer cell migration.

ABSTRACT: The roles of microRNAs (miRNAs) in liver cancer have attracted much attention in recent years. In this study, we demonstrate that miR-520b is downregulated in MHCC-97H cells, a liver cancer cell line with high potential of metastasis, compared with MHCC-97L cells which has a low potential of metastasis. Furthermore, the enhanced expression of miR-520b could inhibit liver cancer cell migration, while silencing its expression resulted in increased migration. Mixed lineage kinase 3 (MLK3) was identified as a direct and functional new target of miR-520b. This regulation was also confirmed by luciferase reporter assays. In addition, our results showed that overexpression of the MLK3 expression partially reversed the effect of miR-520b on liver cancer cell migration, indicating that MLK3 contributes to the migration in liver cancer. The newly identified miR-520b/MLK3 axis partially elucidates the molecular mechanism of liver cancer cell migration and represents a new potential therapeutic target for liver cancer treatment.

SUBMITTER: Zhang F

PROVIDER: S-EPMC7098554 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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MLK3 is a newly identified microRNA-520b target that regulates liver cancer cell migration.

Zhang Fei F Zhu Yu Y Wu Shuhua S Hou Guodong G Wu Nianxiang N Qian Lirun L Yang Dong D

PloS one 20200326 3

The roles of microRNAs (miRNAs) in liver cancer have attracted much attention in recent years. In this study, we demonstrate that miR-520b is downregulated in MHCC-97H cells, a liver cancer cell line with high potential of metastasis, compared with MHCC-97L cells which has a low potential of metastasis. Furthermore, the enhanced expression of miR-520b could inhibit liver cancer cell migration, while silencing its expression resulted in increased migration. Mixed lineage kinase 3 (MLK3) was ident ...[more]

PMID: 32214367

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Project description:To date, the role of hematopoietic-substrate-1-associated protein X-1 (HAX1) in liver cancer is rarely studied. The present study explored the role of HAX1 in liver cancer. The association between HAX1 expression and survival of patients with liver cancer was analyzed by a log-rank test. The target genes for HAX1 was predicted by TargetScan and verified by a dual-luciferase reporter assay. The protein and mRNA expressions of HAX1 in liver cancer and adjacent non-cancerous tissues were examined by immunohistochemistry and reverse transcription-quantitative PCR (RT-qPCR). The transfection efficiency of HAX1, small interfering RNA against HAX1, microRNA (miR)-125a mimics, miR-125a inhibitor, miR-223 mimics and miR-223 inhibitor in liver cancer cells was determined by RT-qPCR. The expression of HAX1, p53, VEGF, epithelial-to-mesenchymal transition (EMT)-related markers (E-cadherin, N-cadherin and vimentin) in the cancer cells were determined by western blotting and RT-qPCR. Cell viability, migration, invasion and colony formation rates were determined by Cell Counting Kot-8, wound healing, Transwell and colony formation assays, respectively. The results showed that high expression of HAX1 in liver cancer was found relate to poor prognosis in patients with liver cancer, and upregulation of HAX1 expression in liver cancer tissues was related to lower overall survival. miR-125a-5p directly binds to HAX1. Upregulation of miR-125a-5p expression inhibited cell viability, migration, invasion and colony formation of SK-Hep1 cells and reduced the expression of HAX1, VEGF, N-cadherin and vimentin, but increased cell apoptosis and the expression of p53 and E-cadherin. However, the effects miR-125a-5p upregulation were partially reversed by SK-Hep1 cells with HAX1 overexpression. Downregulated miR-125a-5p in SNU-387 cells produced opposite effects, which was partially reversed by HAX silencing. In conclusion, miR-125a-5p suppresses liver cancer growth via targeting HAX1 and concurrently modulating the expression of p53 and VEGF and EMT-related markers.

Project description:Despite investigations into microRNA (miRNA) expression in esophageal cancer (EC) tissue, miRNAs that participate in EC pathogenesis and their subsequent mechanisms of action remain to be determined. The present study aimed to identify important miRNAs that contribute to EC development, and to assess miRNA biomarkers that could be used in EC diagnosis, prognosis and therapy. Bioinformatics analysis was performed to reanalyze EC tissue miRNA expression microarray dataset GSE113776, which was followed by in vitro verification of miRNA functions using reverse transcription?quantitative PCR, western blot analysis and a dual?luciferase reporter assay. Out of 93 miRNAs extracted, only miR?200a was significantly increased in EC tissues. Transfection of KYSE150 esophageal squamous cell carcinoma (ESCC) cells with miR?200a mimics significantly increased their proliferative, migratory and invasive ability, whereas the opposite cell behaviors were observed in ESCC cells transfected with a miR?200a inhibitor. A total of six miR?200a target genes [catenin ?1 (CTNNB1), cadherin?1 (CDH1), PTEN, adenomatous polyposis coli (APC), catenin ?1 (CTNNA1) and superoxide dismutase 2 (SOD2)] were selected for further analysis based on Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein?protein interaction network map data and protein expression in esophageal tissue. These target genes were downregulated under miR?200a expression and upregulated in the presence of the miR?200a inhibitor. The association between miR?200a and the 3'?untranslated region of target genes in ESCC cells was confirmed using a dual?luciferase reporter assay. In conclusion, the present study demonstrated that miR?200a may participate in the promotion of ESCC cell proliferation, migration and invasion, and provided novel evidence for the direct interaction between miR?200a and CTNNB1, CDH1, PTEN, APC, CTNNA1 and SOD2, which may contribute to the observed altered cell behavior.

Dataset Information

MLK3 is a newly identified microRNA-520b target that regulates liver cancer cell migration.

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MLK3 is a newly identified microRNA-520b target that regulates liver cancer cell migration.

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