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Pleiotropic actions of mIR-21 highlight the critical role of deregulated stromal microRNA's during colorectal cancer progression

Pleiotropic actions of mIR-21 highlight the critical role of deregulated stromal microRNA's during colorectal cancer progression
Pleiotropic actions of mIR-21 highlight the critical role of deregulated stromal microRNA's during colorectal cancer progression
The oncogene microRNA-21 (miRNA; miR-21) is overexpressed in most solid organ tumours; however, a recent examination of stage II colorectal cancer (CRC) specimens suggests this may be a stromal phenomenon and not only a feature of cancer cells. In vitro and in vivo studies show that miR-21 has potent pro-metastatic effects in various malignant carcinoma cell lines. The tumour microenvironment has also been identified as a key actor during the metastatic cascade; however to date the significance of deregulated miR-21 expression within the cancer-associated stroma has not been examined. In the present study, a quantitative RT-PCR-based analysis of laser microdissected tissue confirmed that miR-21 expression is associated with a four-fold mean increase in CRC stroma compared with normal tissue. In situ hybridisation using locked nucleic acid probes localised miR-21 expression predominantly to fibroblasts within tumour-associated stroma. To study the molecular and biological impact of deregulated stromal miR-21 in CRC, stable ectopic expression was induced in immortalised fibroblasts. This resulted in upregulated ?-smooth muscle actin expression implying miR-21 overexpression is driving the fibroblast-to-myofibroblast transdifferentiation. Conditioned medium from miR-21-overexpressing fibroblasts protected CRC cells from oxaliplatin-induced apoptosis and increased their proliferative capacity. 3D organotypic co-cultures containing fibroblasts and CRC cells revealed that ectopic stromal miR-21 expression was associated with increased epithelial invasiveness. Reversion-inducing cysteine-rich protein with kazal motifs, an inhibitor of matrix-remodelling enzyme MMP2, was significantly downregulated by ectopic miR-21 in established and primary colorectal fibroblasts with a reciprocal rise in MMP2 activity. Inhibition of MMP2 abrogated the invasion-promoting effects of ectopic miR-21. This data, which characterises a novel pro-metastatic mechanism mediated by miR-21 in the CRC stroma, highlights the importance of miRNA deregulation within the tumour microenvironment and identifies a potential application for stromal miRNAs as biomarkers in cancer.
2041-4889
e684
Bullock, M.D.
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Pickard, Karen M.
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Nielsen, B.S
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Sayan, A.E.
d1dbbcad-9c53-47c1-8b7e-1b45cc56e077
Jenei, Veronika
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Mellone, Max
7013bff2-2c19-45c4-9ef4-c3aa18799a3d
Mitter, R.
dada2010-a5e1-4dd7-8bbd-aa52104f997e
Primrose, J.N.
d85f3b28-24c6-475f-955b-ec457a3f9185
Thomas, Gareth J.
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Packham, Graham
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Mirnezami, Alex H.
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Bullock, M.D.
1c251c82-7dc6-4df8-9ba2-6b55a4daf947
Pickard, Karen M.
e5188669-dff1-49c7-9c6f-8122b0c74bd9
Nielsen, B.S
67e35144-4538-4a46-a6f3-d9a0c7835cb9
Sayan, A.E.
d1dbbcad-9c53-47c1-8b7e-1b45cc56e077
Jenei, Veronika
04d82852-7d30-458a-bc0b-f00ae6c5dd52
Mellone, Max
7013bff2-2c19-45c4-9ef4-c3aa18799a3d
Mitter, R.
dada2010-a5e1-4dd7-8bbd-aa52104f997e
Primrose, J.N.
d85f3b28-24c6-475f-955b-ec457a3f9185
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Mirnezami, Alex H.
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Bullock, M.D., Pickard, Karen M., Nielsen, B.S, Sayan, A.E., Jenei, Veronika, Mellone, Max, Mitter, R., Primrose, J.N., Thomas, Gareth J., Packham, Graham and Mirnezami, Alex H. (2013) Pleiotropic actions of mIR-21 highlight the critical role of deregulated stromal microRNA's during colorectal cancer progression. Cell Death and Disease, 4, e684. (doi:10.1038/cddis.2013.213). (PMID:23788041)

Record type: Article

Abstract

The oncogene microRNA-21 (miRNA; miR-21) is overexpressed in most solid organ tumours; however, a recent examination of stage II colorectal cancer (CRC) specimens suggests this may be a stromal phenomenon and not only a feature of cancer cells. In vitro and in vivo studies show that miR-21 has potent pro-metastatic effects in various malignant carcinoma cell lines. The tumour microenvironment has also been identified as a key actor during the metastatic cascade; however to date the significance of deregulated miR-21 expression within the cancer-associated stroma has not been examined. In the present study, a quantitative RT-PCR-based analysis of laser microdissected tissue confirmed that miR-21 expression is associated with a four-fold mean increase in CRC stroma compared with normal tissue. In situ hybridisation using locked nucleic acid probes localised miR-21 expression predominantly to fibroblasts within tumour-associated stroma. To study the molecular and biological impact of deregulated stromal miR-21 in CRC, stable ectopic expression was induced in immortalised fibroblasts. This resulted in upregulated ?-smooth muscle actin expression implying miR-21 overexpression is driving the fibroblast-to-myofibroblast transdifferentiation. Conditioned medium from miR-21-overexpressing fibroblasts protected CRC cells from oxaliplatin-induced apoptosis and increased their proliferative capacity. 3D organotypic co-cultures containing fibroblasts and CRC cells revealed that ectopic stromal miR-21 expression was associated with increased epithelial invasiveness. Reversion-inducing cysteine-rich protein with kazal motifs, an inhibitor of matrix-remodelling enzyme MMP2, was significantly downregulated by ectopic miR-21 in established and primary colorectal fibroblasts with a reciprocal rise in MMP2 activity. Inhibition of MMP2 abrogated the invasion-promoting effects of ectopic miR-21. This data, which characterises a novel pro-metastatic mechanism mediated by miR-21 in the CRC stroma, highlights the importance of miRNA deregulation within the tumour microenvironment and identifies a potential application for stromal miRNAs as biomarkers in cancer.

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Published date: 20 June 2013
Organisations: Cancer Sciences

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Local EPrints ID: 359540
URI: https://eprints.soton.ac.uk/id/eprint/359540
ISSN: 2041-4889
PURE UUID: 3a7e1c42-c99c-4c37-aaee-99914961af3f
ORCID for J.N. Primrose: ORCID iD orcid.org/0000-0002-2069-7605
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 06 Nov 2013 14:38
Last modified: 31 Jan 2019 01:37

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Contributors

Author: M.D. Bullock
Author: Karen M. Pickard
Author: B.S Nielsen
Author: A.E. Sayan
Author: Veronika Jenei
Author: Max Mellone
Author: R. Mitter
Author: J.N. Primrose ORCID iD
Author: Graham Packham ORCID iD

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