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miR-19-mediated inhibition of transglutaminase-2 leads to enhanced invasion and metastasis in colorectal cancer

miR-19-mediated inhibition of transglutaminase-2 leads to enhanced invasion and metastasis in colorectal cancer
miR-19-mediated inhibition of transglutaminase-2 leads to enhanced invasion and metastasis in colorectal cancer
Transglutaminase-2 (TG2) is a critical cross-linking enzyme in the extracellular matrix (ECM) and tumor microenvironment (TME). Although its expression has been linked to colorectal cancer, its functional role in the processes that drive disease appears to be context dependent. There is now considerable evidence of a role for microRNAs (miRNA) in the development and progression of cancer, including metastasis. A cell model of metastatic colon adenocarcinoma was used to investigate the contribution of miRNAs to the differential expression of TG2, and functional effects on inflammatory and invasive behavior. The impact of TG2 in colorectal cancer was analyzed in human colorectal tumor specimens and by manipulations in SW480 and SW620 cells. Effects on invasive behavior were measured using Transwell invasion assays, and cytokine production was assessed by ELISA. TG2 was identified as a target for miR-19 by in silico analysis, which was confirmed experimentally. Functional effects were evaluated by overexpression of pre-miR-19a in SW480 cells. Expression of TG2 correlated inversely with invasive behavior, with knockdown in SW480 cells leading to enhanced invasion, and overexpression in SW620 cells the opposite. TG2 expression was observed in colorectal cancer primary tumors but lost in liver metastases. Finally, miR-19 overexpression and subsequent decreased TG2 expression was linked to chromosome-13 amplification events, leading to altered invasive behavior in colorectal cancer cells.

IMPLICATIONS: Chromosome-13 amplification in advanced colorectal cancer contributes to invasion and metastasis by upregulating miR-19, which targets TG2.
1541-7786
1095-1105
Cellura, D.
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Pickard, K.
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Quaratino, S.
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Parker, H.
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Strefford, J.C.
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Thomas, G.J.
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Mitter, R.
dada2010-a5e1-4dd7-8bbd-aa52104f997e
Mirnezami, A.H.
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Peake, N.J.
5865b85c-5698-42a3-b54f-fc036ed87e42
Cellura, D.
e4cffc4c-0e12-40e7-ad13-e90e3fb55332
Pickard, K.
e5188669-dff1-49c7-9c6f-8122b0c74bd9
Quaratino, S.
e111fc36-bc7e-461b-996d-849e97c51e44
Parker, H.
33e0cd81-d45f-49bc-9539-09345d79d895
Strefford, J.C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Thomas, G.J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Mitter, R.
dada2010-a5e1-4dd7-8bbd-aa52104f997e
Mirnezami, A.H.
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Peake, N.J.
5865b85c-5698-42a3-b54f-fc036ed87e42

Cellura, D., Pickard, K., Quaratino, S., Parker, H., Strefford, J.C., Thomas, G.J., Mitter, R., Mirnezami, A.H. and Peake, N.J. (2015) miR-19-mediated inhibition of transglutaminase-2 leads to enhanced invasion and metastasis in colorectal cancer. Molecular Cancer Research, 13 (7), 1095-1105. (doi:10.1158/1541-7786.MCR-14-0466). (PMID:25934693)

Record type: Article

Abstract

Transglutaminase-2 (TG2) is a critical cross-linking enzyme in the extracellular matrix (ECM) and tumor microenvironment (TME). Although its expression has been linked to colorectal cancer, its functional role in the processes that drive disease appears to be context dependent. There is now considerable evidence of a role for microRNAs (miRNA) in the development and progression of cancer, including metastasis. A cell model of metastatic colon adenocarcinoma was used to investigate the contribution of miRNAs to the differential expression of TG2, and functional effects on inflammatory and invasive behavior. The impact of TG2 in colorectal cancer was analyzed in human colorectal tumor specimens and by manipulations in SW480 and SW620 cells. Effects on invasive behavior were measured using Transwell invasion assays, and cytokine production was assessed by ELISA. TG2 was identified as a target for miR-19 by in silico analysis, which was confirmed experimentally. Functional effects were evaluated by overexpression of pre-miR-19a in SW480 cells. Expression of TG2 correlated inversely with invasive behavior, with knockdown in SW480 cells leading to enhanced invasion, and overexpression in SW620 cells the opposite. TG2 expression was observed in colorectal cancer primary tumors but lost in liver metastases. Finally, miR-19 overexpression and subsequent decreased TG2 expression was linked to chromosome-13 amplification events, leading to altered invasive behavior in colorectal cancer cells.

IMPLICATIONS: Chromosome-13 amplification in advanced colorectal cancer contributes to invasion and metastasis by upregulating miR-19, which targets TG2.

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Cellura et al., 2015.pdf - Accepted Manuscript
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Accepted/In Press date: 15 March 2015
e-pub ahead of print date: 1 May 2015
Published date: July 2015
Organisations: Cancer Sciences

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Local EPrints ID: 380003
URI: http://eprints.soton.ac.uk/id/eprint/380003
ISSN: 1541-7786
PURE UUID: a3616e07-dcbd-4f9d-8232-6dc66365c00f
ORCID for H. Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for J.C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

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Date deposited: 01 Sep 2015 10:59
Last modified: 15 Oct 2019 00:45

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Contributors

Author: D. Cellura
Author: K. Pickard
Author: S. Quaratino
Author: H. Parker ORCID iD
Author: J.C. Strefford ORCID iD
Author: G.J. Thomas
Author: R. Mitter
Author: A.H. Mirnezami
Author: N.J. Peake

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