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

PLoS One. 2021 Nov 19;16(11):e0260327. doi: 10.1371/journal.pone.0260327. eCollection 2021.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cancer Survivors
  • Cell Proliferation / genetics
  • Cohort Studies
  • Down-Regulation / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • GTPase-Activating Proteins / genetics
  • Gene Expression / genetics
  • Humans
  • Lymph Nodes / pathology
  • MicroRNAs / genetics*
  • Signal Transduction / genetics*
  • Tumor Suppressor Proteins / genetics*

Substances

  • Biomarkers, Tumor
  • GTPase-Activating Proteins
  • MIRN21 microRNA, human
  • MicroRNAs
  • Tumor Suppressor Proteins

Grants and funding

This research was funded by grants to IR, RBB, BAA, OTJ and AdAr from the Icelandic Centre for Research (grant number 152530-051, www.rannis.is), The Scientific Fund of Landspitali – The National University Hospital in Iceland (grant numbers A-2016-033 and A-2019-042, www.landspitali.is), The Scientific Fund of The Icelandic Cancer Society (year 2017, www.krabb.is/english/), Gongum saman (https://gongumsaman.is/; years 2013 and 2017) and a grant to ArAm and IR from Gongum saman in 2018. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.