Dataset Information

A regulatory network comprising let-7 miRNA and SMUG1 is associated with good prognosis in breast cancer survival

ABSTRACT: Cytosine deamination to uracil in DNA leads to mutations if the DNA lesion is not corrected. Base excision repair (BER) initiated by single-strand selective uracil-DNA glycosylase 1 (SMUG1) primarily recognizes uracil and oxidized pyrimidines, and processes them to restore the correct bases. SMUG1 status has been associated with cancer risk and therapeutic response as high levels of SMUG1 were observed in breast carcinomas and other cancer types. The role of SMUG1 in breast cancer is not completely understood. Here, we define a bad prognosis signature for SMUG1 interactors in different cancers by mapping out a SMUG1 interaction network. Survival analyses of patient outcomes show that high expression of genes in the bad prognosis network correlates with lower survival probability in breast cancer. Interestingly, bioinformatics analyses suggested let-7b-5p microRNA as one of the upstream regulators of SMUG1 interactors. Expression of SMUG1 and let-7b-5p are negatively correlated in breast cancer and we observed an inhibitory auto-regulatory loop between SMUG1 and let-7b-5p in MCF-7 cells. Hence, SMUG1 is a key player connecting RNA and DNA metabolism with regulation of gene expression.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Bernd Thiede

LAB HEAD: Bernd Thiede

PROVIDER: PXD025929 | Pride | 2023-03-09

REPOSITORIES: Pride

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A regulatory network comprising let-7 miRNA and SMUG1 is associated with good prognosis in ER+ breast tumours.

Lirussi Lisa L Ayyildiz Dilara D Liu Yan Y Montaldo Nicola P NP Carracedo Sergio S Aure Miriam R MR Jobert Laure L Tekpli Xavier X Touma Joel J Sauer Torill T Dalla Emiliano E Kristensen Vessela N VN Geisler Jürgen J Piazza Silvano S Tell Gianluca G Nilsen Hilde H

Nucleic acids research 20221001 18

Single-strand selective uracil-DNA glycosylase 1 (SMUG1) initiates base excision repair (BER) of uracil and oxidized pyrimidines. SMUG1 status has been associated with cancer risk and therapeutic response in breast carcinomas and other cancer types. However, SMUG1 is a multifunctional protein involved, not only, in BER but also in RNA quality control, and its function in cancer cells is unclear. Here we identify several novel SMUG1 interaction partners that functions in many biological processes ...[more]

PMID: 36156150

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Project description:Breast cancer (BC) is a commonly identified life-threatening type of cancer and a major cause of death among women worldwide. Several microRNAs (miRs), including miR-143-5p, have been reported to be vital for regulating hallmarks of cancer; however, the effect of miR-143-5p on BC requires further exploration. The present study performed bioinformatics analysis on GSE42072 and GSE41922 datasets from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database to identify miR-143-5p expression patterns. Furthermore, miR-143-5p expression was detected in BC cell lines and tissues via reverse transcription-quantitative PCR. Post-transfection with miR-143-5p mimics, Cell Counting Kit-8, colony formation and Transwell assays were performed to explore the effects of miR-143-5p on BC cell proliferation, colony formation, and migration. The association of miR-143-5p with the hypoxia-inducible factor-1α (HIF-1α)-associated glucose transporter 1 (GLUT1) pathway was explored via western blotting, immunofluorescence and dual-luciferase reporter assay. The present study detected high expression of miR-143-5p in BC tissue of the GSE42072 and serum of the GSE41922 datasets by GEO chip analysis. Additionally, the expression levels of miR-143-5p were decreased in BC tissues compared with those in adjacent healthy tissues, and low miR-143-5p expression was associated with a poorer prognosis and shorter survival time in patients with BC. In vitro, miR-143-5p expression levels were decreased in BC cells, and transfection with miR-143-5p mimics suppressed BC cell proliferation, colony formation, migration. Furthermore, miR-143-5p targeted the HIF-1α-related GLUT1 pathway, and inhibited HIF-1α and GLUT1 expression. Additionally, HIF-1α agonists reversed the miR-143-5p-induced inhibition during tumorigenesis. In conclusion, miR-143-5p exhibited low expression in BC tissues, and suppressed BC cell proliferation, colony formation, migration. Moreover, the antitumor effects of miR-143-5p targeted the HIF-1α-related GLUT1 pathway.

Project description:Background: The global effect of copy number and epigenetic alterations on miRNA expression in cancer is poorly understood. In the present study, we integrate genome-wide copy number, DNA methylation and miRNA expression and identify genetic mechanisms underlying miRNA dysregulation in breast cancer. Results: We identify 70 miRNAs whose expression was associated with aberrations in copy number or methylation, or both. Among these, five miRNA families are represented. Interestingly, the members of these families are encoded on different chromosomes and are complementarily altered by gain or hypomethylation across the patients. In an independent breast cancer cohort of 123 patients, 41 of the 70 miRNAs were confirmed with respect to aberration pattern and association to expression. In vitro functional experiments were performed in breast cancer cell lines with miRNA mimics to evaluate the phenotype of the replicated miRNAs. let-7e-3p, which in tumors is found associated with hypermethylation, is shown to induce apoptosis and reduce cell viability, and low let-7e-3p expression is associated with poorer prognosis. The overexpression of three other miRNAs associated with copy number gain, miR-21-3p, miR-148b-3p and miR-151a-5p, increases proliferation of breast cancer cell lines. In addition, miR-151a-5p enhances the levels of phosphorylated AKT protein. Conclusions: Our data provide novel evidence of the mechanisms behind miRNA dysregulation in breast cancer. The study contributes to the understanding of how methylation and copy number aberrations influence miRNA expression, emphasizing miRNA functionality through redundant encoding, and suggests novel miRNAs important in breast cancer. The miRNA expression profiling of 149 breast cancer samples was performed using the 8x15k “Human miRNA Microarray Kit (V2)” with design id 019118 from Agilent (Agilent Technologies, Santa Clara, CA, USA). In brief, 100 ng total RNA was dephosphorylated, labeled and hybridized for 20 hours, following the manufacturer’s protocol. Scanning was performed on Agilent Scanner G2565A, signals were extracted using Feature Extraction v9.5 and the subsequent data processing was performed using the GeneSpring software v12.0 (Agilent Technologies). In brief, the miRNA signal intensities were log2-transformed and normalized to the 90th percentile, and miRNAs that were detected in less than 10% of the samples were excluded. This resulted in 448 unique mature miRNAs.

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