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The miR-28-5p Targetome Discovery Identified SREBF2 as One of the Mediators of the miR-28-5p Tumor Suppressor Activity in Prostate Cancer Cells.

ABSTRACT: miR-28-5p is downregulated in some tumor tissues in which it has been demonstrated to have tumor suppressor (TS) activity. Here, we demonstrate that miR-28-5p acts as a TS in prostate cancer (PCa) cells affecting cell proliferation/survival, as well as migration and invasion. Using the miRNA pull out assay and next generation sequencing, we collected the complete repertoire of miR-28-5p targets, obtaining a data set (miR-28-5p targetome) of 191 mRNAs. Filtering the targetome with TargetScan 7, PITA and RNA22, we found that 61% of the transcripts had miR-28-5p binding sites. To assign a functional value to the captured transcripts, we grouped the miR-28-5p targets into gene families with annotated function and showed that six transcripts belong to the transcription factor category. Among them we selected SREBF2, a gene with an important role in PCa. We validated miR-28-5p/SREBF2 interaction, demonstrating that SREBF2 inhibition affects almost all the tumor processes altered by miR-28-5p re-expression, suggesting that SREBF2 is an important mediator of miR-28-5p TS activity. Our findings support the identification of the targetome of cancer-related miRNAs as a tool to discover genes and pathways fundamental for tumor development, and potential new targets for anti-tumor therapy.

SUBMITTER: Fazio S

PROVIDER: S-EPMC7072282 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The miR-28-5p Targetome Discovery Identified SREBF2 as One of the Mediators of the miR-28-5p Tumor Suppressor Activity in Prostate Cancer Cells.

Fazio Sofia S Berti Gabriele G Russo Francesco F Evangelista Monica M D'Aurizio Romina R Mercatanti Alberto A Pellegrini Marco M Rizzo Milena M

Cells 20200203 2

miR-28-5p is downregulated in some tumor tissues in which it has been demonstrated to have tumor suppressor (TS) activity. Here, we demonstrate that miR-28-5p acts as a TS in prostate cancer (PCa) cells affecting cell proliferation/survival, as well as migration and invasion. Using the miRNA pull out assay and next generation sequencing, we collected the complete repertoire of miR-28-5p targets, obtaining a data set (miR-28-5p targetome) of 191 mRNAs. Filtering the targetome with TargetScan 7, P ...[more]

PMID: 32028704

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Project description:MicroRNAs (miRNAs or miRs) play an important role in the tumorigenesis and progression of breast cancer. However, the function of miR?28?5p in breast cancer migration has yet to be determined. In the present study, Human MicroRNA Expression Database (HMED) analysis revealed that the expression level of miR?28?5p was significantly lower in breast cancer tissue than in normal breast tissue. Kaplan-?Meier plotter (KMPLOT) analysis revealed that the low expression level of miR?28?5p was associated with a poor survival in breast cancer. In addition, reverse transcription?quantitative PCR (RT?qPCR) revealed that the expression of miR?28?5p was significantly lower in breast cancer cell lines compared with that in human mammary epithelial cells (HMECs). Moreover, transfection with miR?28?5p mimics suppressed the migration of MCF?7 cells, whereas an miR?28?5p inhibitor exerted the opposite effect. Gene chip assay identified 648 differentially expressed genes (DEGs) in cells overexpressing miR?28?5p. The DEGs are enriched in the 'focal adhesion' and 'pathway in cancer' pathways. The expression levels of Ras?related protein Rap?1b (RAP1B), WD repeat and SOCS box containing 2 (WSB2) and vascular endothelial growth factor A (VEGFA) were confirmed by RT?qPCR. Furthermore, transfection with miR?28?5p mimics decreased WSB2 expression, whereas the miR?28?5p inhibitor increased the expression of WSB2, at both the transcriptional and translational levels. miR?28?5p targets the 3'UTR of WSB2, and the binding site is conserved in multiple species, with a consensus motif of 5'?AGCUCCUU?3'. Moreover, WSB2 overexpression promoted the migration of MCF?7 cells which had been inhibited by miR?28?5p. UALCAN analysis revealed that WSB2 was significantly upregulated in primary breast tumor tissue, and a high expression level of WSB2 was associated with a poor survival in breast cancer. Furthermore, immunohistochemistry revealed that the expression of WSB2 was markedly higher in breast cancer tissue compared with that in adjacent normal breast tissue. Taken together, the findings of the present study demonstrate that miR?28?5p inhibits the migration of breast cancer cells by regulating WSB2 expression, and the miR?28?5p/WSB2 axis may be a novel therapeutic target in breast cancer.

Project description:Background:The association of miR-28-5p with colon cancer remains to be elucidated. This study aimed to determine the clinical significance and prognostic value of miR-28-5p in colon cancer. Methods:We retrospectively analyzed the data of miR-28-5p in colon adenocarcinoma data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and the data was divided into cancer group and normal group, respectively. Forty colon cancer tissues and adjacent normal tissues were collected and tested by qRT-PCR methods. The difference of the miR-28-5p expression between colon cancer and normal tissues was compared. The clinical significance of miR-28-5p in colon cancer and the association with the survival were determined. The predictive value of miR-28-5p in clinical features was determined using receiver operating characteristic curve. The target genes of miR-28-5p were identified, and the functional of target genes was performed using bioinformatics analysis. Results:: The expression of miR-28-5p was increased in colon cancer tissues compared with normal controls (p = 0.037). The expression of miR-28-5p was significantly increased in tissues with distant metastases compared with that without distant metastases (p = 0.026). Patients with high expression of miR-28-5p have a shorter survival time than those with low expression (p = 0.004). Cox analysis showed that miR-28-5p was an independent predictor for the survival of patients (p = 0.014). Combination of miR-28-5p with TNM stage and clinical stage can improve the prognostic value for the patients (p < 0.05). miR-28-5p has a moderate predictive value in predicting the TNM stage and clinical stage (T stage: AUC = 0.515; N stage: AUC = 0.523, M stage: AUC = 0.572; clinical stage: AUC = 0.539). 711 potential target genes of miR-28-5p were screened; their function and pathways were identified. Conclusions:: This study demonstrated that miR-28-5p was increased in colon cancer and can be an independent indicator for the overall survival in patients with colon cancer.

Dataset Information

The miR-28-5p Targetome Discovery Identified SREBF2 as One of the Mediators of the miR-28-5p Tumor Suppressor Activity in Prostate Cancer Cells.

Publications

The miR-28-5p Targetome Discovery Identified SREBF2 as One of the Mediators of the miR-28-5p Tumor Suppressor Activity in Prostate Cancer Cells.

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