MicroRNAs-143 and -145 induce epithelial to mesenchymal transition and modulate the expression of junction proteins

L Avalle, D Incarnato, A Savino, M Gai, F Marino, S Pensa, I Barbieri, MB Stadler, P Provero, Salvatore Oliviero, Valeria Poli

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Transforming growth factor (TGF)-β is one of the major inducers of epithelial to mesenchymal transition (EMT), a crucial program that has a critical role in promoting carcinoma's metastasis formation. MicroRNAs-143 and -145, which are both TGF-β direct transcriptional targets, are essential for the differentiation of vascular smooth muscle cells (VSMC) during embryogenesis, a TGF-β-dependent process reminiscent of EMT. Their role in adult tissues is however less well defined and even ambiguous, as their expression was correlated both positively and negatively with tumor progression. Here we show that high expression of both miRs-143 and -145 in mouse mammary tumor cells expressing constitutively active STAT3 (S3C) is involved in mediating their disrupted cell-cell junctions. Additionally, miR-143 appears to have a unique role in tumorigenesis by enhancing cell migration in vitro and extravasation in vivo while impairing anchorage-independent growth, which may explain the contradictory reports about its role in tumors. Accordingly, we demonstrate that overexpression of either miRNA in the non-transformed mammary epithelial NMuMG cells leads to upregulation of EMT markers and of several endogenous TGF-β targets, downmodulation of a number of junction proteins and increased motility, correlating with enhanced basal and TGF-β-induced SMAD-mediated transcription. Moreover, pervasive transcriptome perturbation consistent with the described phenotype was observed. In particular, the expression of several transcription factors involved in the mitogenic responses, of MAPK family members and, importantly, of several tight junction proteins and the SMAD co-repressor TGIF was significantly reduced. Our results provide important mechanistic insight into the non-redundant role of miRs-143 and -145 in EMT-related processes in both transformed and non-transformed cells, and suggest that their expression must be finely coordinated to warrant optimal migration/invasion while not interfering with cell growth. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/17.
Original languageEnglish
Pages (from-to)1750-1760
Number of pages11
JournalCell Death and Differentiation
Volume24
Issue number10
DOIs
Publication statusPublished - 2017

Fingerprint

Epithelial-Mesenchymal Transition
Transforming Growth Factors
MicroRNAs
Proteins
Molecular Motor Proteins
Tight Junction Proteins
Co-Repressor Proteins
Intercellular Junctions
Growth
Vascular Smooth Muscle
Transcriptome
Smooth Muscle Myocytes
Embryonic Development
Cell Movement
Neoplasms
Carcinogenesis
Breast
Transcription Factors
Up-Regulation
Epithelial Cells

Cite this

MicroRNAs-143 and -145 induce epithelial to mesenchymal transition and modulate the expression of junction proteins. / Avalle, L; Incarnato, D; Savino, A; Gai, M; Marino, F; Pensa, S; Barbieri, I; Stadler, MB; Provero, P; Oliviero, Salvatore; Poli, Valeria.

In: Cell Death and Differentiation, Vol. 24, No. 10, 2017, p. 1750-1760.

Research output: Contribution to journalArticle

Avalle, L, Incarnato, D, Savino, A, Gai, M, Marino, F, Pensa, S, Barbieri, I, Stadler, MB, Provero, P, Oliviero, S & Poli, V 2017, 'MicroRNAs-143 and -145 induce epithelial to mesenchymal transition and modulate the expression of junction proteins', Cell Death and Differentiation, vol. 24, no. 10, pp. 1750-1760. https://doi.org/10.1038/cdd.2017.103
Avalle, L ; Incarnato, D ; Savino, A ; Gai, M ; Marino, F ; Pensa, S ; Barbieri, I ; Stadler, MB ; Provero, P ; Oliviero, Salvatore ; Poli, Valeria. / MicroRNAs-143 and -145 induce epithelial to mesenchymal transition and modulate the expression of junction proteins. In: Cell Death and Differentiation. 2017 ; Vol. 24, No. 10. pp. 1750-1760.
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AU - Incarnato, D

AU - Savino, A

AU - Gai, M

AU - Marino, F

AU - Pensa, S

AU - Barbieri, I

AU - Stadler, MB

AU - Provero, P

AU - Oliviero, Salvatore

AU - Poli, Valeria

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AB - Transforming growth factor (TGF)-β is one of the major inducers of epithelial to mesenchymal transition (EMT), a crucial program that has a critical role in promoting carcinoma's metastasis formation. MicroRNAs-143 and -145, which are both TGF-β direct transcriptional targets, are essential for the differentiation of vascular smooth muscle cells (VSMC) during embryogenesis, a TGF-β-dependent process reminiscent of EMT. Their role in adult tissues is however less well defined and even ambiguous, as their expression was correlated both positively and negatively with tumor progression. Here we show that high expression of both miRs-143 and -145 in mouse mammary tumor cells expressing constitutively active STAT3 (S3C) is involved in mediating their disrupted cell-cell junctions. Additionally, miR-143 appears to have a unique role in tumorigenesis by enhancing cell migration in vitro and extravasation in vivo while impairing anchorage-independent growth, which may explain the contradictory reports about its role in tumors. Accordingly, we demonstrate that overexpression of either miRNA in the non-transformed mammary epithelial NMuMG cells leads to upregulation of EMT markers and of several endogenous TGF-β targets, downmodulation of a number of junction proteins and increased motility, correlating with enhanced basal and TGF-β-induced SMAD-mediated transcription. Moreover, pervasive transcriptome perturbation consistent with the described phenotype was observed. In particular, the expression of several transcription factors involved in the mitogenic responses, of MAPK family members and, importantly, of several tight junction proteins and the SMAD co-repressor TGIF was significantly reduced. Our results provide important mechanistic insight into the non-redundant role of miRs-143 and -145 in EMT-related processes in both transformed and non-transformed cells, and suggest that their expression must be finely coordinated to warrant optimal migration/invasion while not interfering with cell growth. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/17.

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