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Role of miR-214 in regulation of ?-catenin and the malignant phenotype of melanoma.

ABSTRACT: Wnt/?-catenin signaling plays an important role in melanocyte biology, especially in the early stages of melanocyte transformation and melanomagenesis. ?-catenin, encoded by the gene CTNNB1, is an intracellular signal transducer of Wnt signaling and activates transcription of genes important for cell proliferation and survival. Wnt/?-catenin signaling is frequently activated in melanoma through oncogenic mutations of ?-catenin and elevated ?-catenin levels are positively correlated with melanoma aggressiveness. Molecular mechanisms that regulate ?-catenin expression in melanoma are not fully understood. MicroRNA-214 is known to function as a tumor suppressor by targeting ?-catenin in several types of cancer cells. Here, we investigated the regulation of ?-catenin by miR-214 and its role in melanoma. We show that ?-catenin mRNA levels are negatively correlated with miR-214 in melanoma. However, overexpression of miR-214 paradoxically increased ?-catenin protein levels and promoted malignant properties of melanoma cells including resistance to mitogen-activated protein kinase inhibitors (MAPKi). RNA-seq analysis revealed that melanoma cells predominantly express a ?-catenin mRNA isoform lacking miR-214 target site. Using matched miRNA and mRNA-seq and bioinformatics analysis, we identified novel miR-214 targets, ankyrin repeat domain 6 (ANKRD6) and C-terminal binding protein 1 (CTBP1), that are involved in negative regulation of Wnt signaling. Overexpression of miR-214 or knockdown of the novel miR-214 targets, ANKRD6 or CTBP1, increased melanoma cell proliferation, migration, and decreased sensitivity to MAPKi. Our data suggest that in melanoma cells ?-catenin is not regulated by miR-214 and the functions of miR-214 in melanoma are mediated partly by regulating proteins involved in attenuation of Wnt/?-catenin signaling.

SUBMITTER: Prabhakar K

PROVIDER: S-EPMC6800786 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Role of miR-214 in regulation of β-catenin and the malignant phenotype of melanoma.

Prabhakar Kirthana K Rodrίguez Carlos I CI Jayanthy Ashika S AS Mikheil Dareen M DM Bhasker Aishwarya Iyer AI Perera Ranjan J RJ Setaluri Vijayasaradhi V

Molecular carcinogenesis 20190724 11

Wnt/β-catenin signaling plays an important role in melanocyte biology, especially in the early stages of melanocyte transformation and melanomagenesis. β-catenin, encoded by the gene CTNNB1, is an intracellular signal transducer of Wnt signaling and activates transcription of genes important for cell proliferation and survival. Wnt/β-catenin signaling is frequently activated in melanoma through oncogenic mutations of β-catenin and elevated β-catenin levels are positively correlated with melanoma ...[more]

PMID: 31338875

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Project description:The down-regulation of miR-214 has previously been observed in human hepatocellular carcinoma (HCC). Here, we demonstrated the down-regulation of miR-214 is associated with cell invasion, stem-like traits and early recurrence of HCC. Firstly, we validated the suppression of miR-214 in human HCC by real-time quantitative RT-PCR (qRT-PCR) in 20 paired tumor and non-tumor liver tissues of HCC patients and 10 histologically normal liver tissues from colorectal cancer patients with liver metastases. Further qRT-PCR analysis of 50 HCC tissues from an independent cohort of HCC patients of whom 29 with early recurrent disease (<2 years) and 21 with late recurrent disease demonstrated that the suppression of miR-214 was significantly more suppressed in samples from HCC patients with early recurrent disease compared those from patients with no recurrence. Re-expression of miR-214 significantly suppressed the growth of HCC cells in vitro and reduced their tumorigenicity in vivo. The enhancer of zeste homologue 2 (EZH2) and ?-catenin (CTNNB1) was identified as two potential direct downstream targets of miR-214 through bioinformatics analysis and experimentally validated the miRNA-target interactions with a dual-firefly luciferase reporter assay. In corroborate with this, both EZH2 and CTNNB1 are found to be significantly overexpressed in human HCC biopsies. Since EZH2 can regulate CTNNB1, CTNNB1 can also be an indirect target of miR-214 through EZH2. Silencing EZH2 or CTNNB1 expression suppressed the growth and invasion of HCC cells and induced E-cadherin (CDH1), known to inhibit cell invasion and metastasis. Furthermore, the silencing of miR-214 or overexpression of EZH2 increased EpCAM(+) stem-like cells through the activation of CTNNB1. Interestingly, the up-regulation of EZH2, CTNNB1 and the down-regulation of CDH1 in HCC patients correlated with early recurrent disease and can be an independent predictor of poor survival. Therefore, miR-214 can directly or indirectly target CTNNB1 to modulate the ?-catenin signaling pathway in HCC.

Dataset Information

Role of miR-214 in regulation of ?-catenin and the malignant phenotype of melanoma.

Publications

Role of miR-214 in regulation of β-catenin and the malignant phenotype of melanoma.

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