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A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype

A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype
A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype

The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-β signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.

0143-3334
798-807
Melling, Genevieve E.
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Flannery, Sarah E.
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Abidin, Siti A.
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Clemmens, Hannah
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Prajapati, Priyanka
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Hinsley, Emma E.
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Hunt, Stuart
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Catto, James W.F.
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Coletta, Ricardo Della
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Mellone, Massimiliano
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Thomas, Gareth J.
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Parkinson, E. Ken
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Prime, Stephen S.
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Paterson, Ian C.
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Buttle, David J.
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Lambert, Daniel W.
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Melling, Genevieve E.
daf97635-bf41-4e40-8597-af82d3c1828b
Flannery, Sarah E.
4aab6f1c-6e38-42b0-93a4-8bae9dac4f74
Abidin, Siti A.
e67fce15-d5e8-419e-a854-8c77f96feee1
Clemmens, Hannah
9c42530c-3789-440a-adb2-d5b668cdaa70
Prajapati, Priyanka
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Hinsley, Emma E.
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Hunt, Stuart
e8dec857-8250-469b-9ddb-d84e8ddc8d23
Catto, James W.F.
33d9294c-b303-4b88-8635-595e41f5a490
Coletta, Ricardo Della
b587ff79-f0f3-4c33-a044-c330a04b42d9
Mellone, Massimiliano
b0301b32-14f8-4203-9026-b7f90885cab9
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Parkinson, E. Ken
771bb082-07af-4fa6-ac10-a961544045ed
Prime, Stephen S.
87e24c6b-a02b-4704-bb27-c11b40871ab5
Paterson, Ian C.
014fef90-ad00-43a1-9504-f71938030937
Buttle, David J.
a44396a6-5418-419d-bfe6-164f3feabd55
Lambert, Daniel W.
f32446f9-e2ce-49bf-9603-f3351968d417

Melling, Genevieve E., Flannery, Sarah E., Abidin, Siti A., Clemmens, Hannah, Prajapati, Priyanka, Hinsley, Emma E., Hunt, Stuart, Catto, James W.F., Coletta, Ricardo Della, Mellone, Massimiliano, Thomas, Gareth J., Parkinson, E. Ken, Prime, Stephen S., Paterson, Ian C., Buttle, David J. and Lambert, Daniel W. (2018) A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype. Carcinogenesis, 39 (6), 798-807. (doi:10.1093/carcin/bgy032).

Record type: Article

Abstract

The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-β signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.

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More information

Accepted/In Press date: 26 February 2018
e-pub ahead of print date: 28 February 2018
Published date: 28 May 2018

Identifiers

Local EPrints ID: 421565
URI: https://eprints.soton.ac.uk/id/eprint/421565
ISSN: 0143-3334
PURE UUID: f918dce2-5052-4b8a-b645-d9879b7a7e1d
ORCID for Massimiliano Mellone: ORCID iD orcid.org/0000-0002-4964-9340

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Date deposited: 15 Jun 2018 16:30
Last modified: 14 Mar 2019 01:38

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Contributors

Author: Genevieve E. Melling
Author: Sarah E. Flannery
Author: Siti A. Abidin
Author: Hannah Clemmens
Author: Priyanka Prajapati
Author: Emma E. Hinsley
Author: Stuart Hunt
Author: James W.F. Catto
Author: Ricardo Della Coletta
Author: Massimiliano Mellone ORCID iD
Author: E. Ken Parkinson
Author: Stephen S. Prime
Author: Ian C. Paterson
Author: David J. Buttle
Author: Daniel W. Lambert

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