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Mir‐34a and mir‐200c have an additive tumor‐suppressive effect on breast cancer cells and patient prognosis

Authors :
Behzad Baradaran
Pascal H.G. Duijf
Vahid Khaze
Nicola Silvestris
Behzad Mansoori
Dariush Shanehbandi
Ahad Mokhtarzadeh
Afshin Derakhshani
Ali Mohammadi
Elham Baghbani
Mansoori, Behzad
Silvestris, Nicola
Mohammadi, Ali
Khaze, Vahid
Baghbani, Elham
Mokhtarzadeh, Ahad
Shanehbandi, Dariush
Derakhshani, Afshin
Duijf, Pascal HG
Baradaran, Behzad
Source :
Mansoori, B, Silvestris, N, Mohammadi, A, Khaze, V, Baghbani, E, Mokhtarzadeh, A, Shanehbandi, D, Derakhshani, A, Duijf, P H G & Baradaran, B 2021, ' Mir-34a and mir-200c have an additive tumor-suppressive effect on breast cancer cells and patient prognosis ', Genes, vol. 12, no. 2, 267 . https://doi.org/10.3390/genes12020267, Genes, Vol 12, Iss 267, p 267 (2021), Genes, Volume 12, Issue 2
Publication Year :
2021

Abstract

Breast cancer is the most common women’s malignancy in the world and, for subgroups ofpatients, 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-34aand 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 andepithelial-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 therapeuticstrategy for breast cancer patients. 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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Mansoori, B, Silvestris, N, Mohammadi, A, Khaze, V, Baghbani, E, Mokhtarzadeh, A, Shanehbandi, D, Derakhshani, A, Duijf, P H G & Baradaran, B 2021, ' Mir-34a and mir-200c have an additive tumor-suppressive effect on breast cancer cells and patient prognosis ', Genes, vol. 12, no. 2, 267 . https://doi.org/10.3390/genes12020267, Genes, Vol 12, Iss 267, p 267 (2021), Genes, Volume 12, Issue 2
Accession number :
edsair.doi.dedup.....ed1da4cd3ee00607aad2bdf2eb9d530c