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Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways

Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways


Title: Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways
Author: Amirfallah, Arsalan
Knutsdottir, Hildur
Arason, Aðalgeir
Hilmarsdóttir, Bylgja
Jóhannsson, Óskar Þór
Agnarsson, Bjarni Agnar
Barkardottir, Rosa B.
Reynisdottir, Inga   orcid.org/0000-0002-9730-7476
Date: 2021-11-19
Language: English
Scope: 18
University/Institute: University of Iceland
Department: Clinical Laboratory Services, Diagnostics and Blood Bank
Cancer Center
Faculty of Medicine
Series: PLoS ONE; 16(11)
ISSN: 1932-6203
DOI: https://doi.org/10.1371/journal.pone.0260327
Subject: Brjóstakrabbamein; Gen; Náttúrufræðingar; Krabbameinslæknisfræði; Meinafræði; Breast cancer; Breast tumors; Malignant tumors; Tumor suppressor genes; Prostate cancer; Metaanalysis; Breast tissue; Clinical pathology; Multidisciplinary
URI: https://hdl.handle.net/20.500.11815/2763

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Citation:

Amirfallah , A , Knutsdottir , H , Arason , A , Hilmarsdóttir , B , Jóhannsson , Ó Þ , Agnarsson , B A , Barkardottir , R B & Reynisdottir , I 2021 , ' Hsa-miR-21-3p associates with breast cancer patient survival and targets genes in tumor suppressive pathways ' , PLoS ONE , vol. 16 , no. 11 , e0260327 , pp. e0260327 . https://doi.org/10.1371/journal.pone.0260327

Abstract:

Breast cancer is the cancer most often diagnosed in women. MicroRNAs (MIRs) are short RNA molecules that bind mRNA resulting in their downregulation. MIR21 has been shown to be an oncomiR in most cancer types, including breast cancer. Most of the effects of miR-21 have been attributed to hsa-miR-21-5p that is transcribed from the leading strand of MIR21, but hsa-miR-21-3p (miR-21-3p), transcribed from the lagging strand, is much less studied. The aim of the study is to analyze whether expression of miR-21-3p is prognostic for breast cancer. MiR-21-3p association with survival, clinical and pathological characteristics was analyzed in a large breast cancer cohort and validated in three separate cohorts, including TCGA and METABRIC. Analytical tools were also used to infer miR-21-3p function and to identify potential target genes and functional pathways. The results showed that in the exploration cohort, high miR-21-3p levels associated with shorter survival and lymph node positivity. In the three validation cohorts, high miR-21-3p levels associated with pathological characteristics that predict worse prognosis. Specifically, in the largest validation cohort, METABRIC (n = 1174), high miR-21-3p levels associated with large tumors, a high grade, lymph node and HER2 positivity, and shorter breast-cancer-specific survival (HR = 1.38, CI 1.13–1.68). This association remained significant after adjusting for confounding factors. The genes with expression levels that correlated with miR-21-3p were enriched in particular pathways, including the epithelial-to-mesenchymal transition and proliferation. Among the most significantly downregulated targets were MAT2A and the tumor suppressive genes STARD13 and ZNF132. The results from this study emphasize that both 3p- and 5p-arms from a MIR warrant independent study. The data show that miR-21-3p overexpression in breast tumors is a marker of worse breast cancer progression and it affects genes in pathways that drive breast cancer by down-regulating tumor suppressor genes. The results suggest miR-21-3p as a potential biomarker.

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Publisher Copyright: Copyright: © 2021 Amirfallah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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