MiR-205-5p inhibition by locked nucleic acids impairs metastatic potential of breast cancer cells

Antonella De Cola,Vincenzo De Laurenzi,Alessia Lamolinara,Marco Marchisio,Matilde Todaro,Manuela Iezzi,Paola Lanuti,Cosmo Rossi

doi:10.1038/s41419-018-0854-9

Antonella De Cola, Vincenzo De Laurenzi + Show 6 more

Open Access

https://doi.org/10.1038/s41419-018-0854-9

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Abstract

Mir-205 plays an important role in epithelial biogenesis and in mammary gland development but its role in cancer still remains controversial depending on the specific cellular context and target genes. We have previously reported that miR-205-5p is upregulated in breast cancer stem cells targeting ERBB pathway and leading to targeted therapy resistance. Here we show that miR-205-5p regulates tumorigenic properties of breast cancer cells, as well as epithelial to mesenchymal transition. Silencing this miRNA in breast cancer results in reduced tumor growth and metastatic spreading in mouse models. Moreover, we show that miR-205-5p knock-down can be obtained with the use of specific locked nucleic acids oligonucleotides in vivo suggesting a future potential use of this approach in therapy.

Highlights

Despite advances in breast cancer treatment, metastases still remain the major cause of patients death due to therapeutic failure and disease recurrence
Results miR-205-5p regulates the tumorigenic potential of Breast CSCs (BCSCs) Recently we reported that miR-205-5p is overexpressed in BCSCs compared with more differentiated cancer cells and by regulating the expression of different molecules including p63, participates to sustain a stem-like phenotype of breast cancer cells, desensitizing these cells to targeted therapy[17]
We stably knocked down miR-205-5p with short hairpin RNA lentiviral vectors in two patientderived BCSC lines and we examined the effect of miR205 silencing on proliferation in vitro

Summary

Introduction

Despite advances in breast cancer treatment, metastases still remain the major cause of patients death due to therapeutic failure and disease recurrence. It is currently believed that a subpopulation of cells within the tumor displaying stem-like properties, such as self renewal and ability to differentiate, drives tumor progression and metastasis, and is in general more resistant to therapies, leading to a worst clinical outcome[1,2,3,4]. These cells have been indicated as: cancer stem cells (CSCs) or tumorinitiating cells[5]. EMT is reactivated and is promoted by the tumor microenvironment leading to the induction of several transcription factors like Zeb[1] and Snail and to the activation of intracellular signaling pathways[9] enabling cells to move to new sites, allowing the formation of metastatic lesions

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