miR-34a and miR-200c Have an Additive Tumor-Suppressive Effect on Breast Cancer Cells and Patient Prognosis.

Affiliation

Mansoori B(1)(2)(3), Silvestris N(4)(5), Mohammadi A(3), Khaze V(1), Baghbani E(1)(2), Mokhtarzadeh A(1), Shanehbandi D(1), Derakhshani A(1), Duijf PHG(6)(7), Baradaran B(1)(8).
Author information:
(1)Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran.
(2)Student Research Committee, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran.
(3)Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, 5000C Odense, Denmark.
(4)Medical Oncology Unit-IRCCS IstitutoTumori "Giovanni Paolo II" of Bari, 70124 Bari, Italy.
(5)Department of Biomedical Sciences and Human Oncology, DIMO-University of Bari, 70124 Bari, Italy.
(6)Faculty of Health, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, 37 Kent Street, Brisbane, QLD 4102, Australia.
(7)University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, 37 Kent Street, Brisbane, QLD 4102, Australia.
(8)Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166614766, Iran.

Abstract

Breast cancer is the most common women's malignancy in the world and, for subgroups of patients, treatment outcomes remain poor. Thus, more effective therapeutic strategies are urgently needed. MicroRNAs (miRNAs) have emerged as promising therapeutic tools and targets, as they play significant roles in regulating key cellular processes by suppressing gene expression. However, additive opportunities involving miRNAs have been underexplored. For example, both miR-34a and miR-200c individually suppress the development of different types of cancer, but the cellular effects of their combined actions remain unknown. Here, we show that miR-34a and miR-200c levels are reduced in breast tumors compared to adjacent normal tissues and that this additively predicts poor patient survival. In addition, in cell lines, miR-34a and miR-200c additively induce apoptosis and cell cycle arrest, while also inhibiting proliferation, invasion, migration, stemness and epithelial-to-mesenchymal transition (EMT). Mechanistically, both miRNA-34a and miR-200c directly target HIF1-α and subsequently downregulate VEGFR, MMP9 and CXCR4, although combined miRNA-34a and miR-200c delivery suppresses mouse xenograft tumor development as effectively as individual delivery. We establish a model, supported by in vitro and clinical data, which collectively suggest that the co-delivery of miR-34a and miR-200c represents a promising novel therapeutic strategy for breast cancer patients.