miR-153 supports colorectal cancer progression via pleiotropic effects that enahance invasion and chemotherapeutic resistance
miR-153 supports colorectal cancer progression via pleiotropic effects that enahance invasion and chemotherapeutic resistance
Although microRNAs (miRNA) have been broadly studied in cancer, comparatively less is understood about their role in progression. Here we report that miR-153 has a dual role during progression of colorectal cancer by enhancing cellular invasiveness and platinum-based chemotherapy resistance. miRNA profiling revealed that miR-153 was highly expressed in a cellular model of advanced stage colorectal cancer. Its upregulation was also noted in primary human colorectal cancer compared with normal colonic epithelium and in more advanced colorectal cancer stages compared with early stage disease. In colorectal cancer patients followed for 50 months, 21 of 30 patients with high levels of miR-153 had disease progression compared with others in this group with low levels of miR-153. Functional studies revealed that miR-153 upregulation increased colorectal cancer invasiveness and resistance to oxaliplatin and cisplatin both in vitro and in vivo. Mechanistic investigations indicated that miR-153 promoted invasiveness indirectly by inducing matrix metalloprotease enzyme 9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor Forkhead box O3a (FOXO3a). In support of the latter finding, we found that levels of miR-153 and FOXO3a were inversely correlated in matched human colorectal cancer specimens. Our findings establish key roles for miR-153 overexpression in colorectal cancer progression, rationalizing therapeutic strategies to target expression of this miRNA for colorectal cancer treatment.
6435-6447
Zhang, L.
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Pickard, K.
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Bullock, M.D.
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Jenei, V.
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Strefford, J.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Mitter, R.
dada2010-a5e1-4dd7-8bbd-aa52104f997e
Kelly, G.
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Primrose, J.N.
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Thomas, G.
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Packham, G.K.
fdabe56f-2c58-469c-aadf-38878f233394
Mirnezami, A.H.
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
21 October 2013
Zhang, L.
1170f035-b8d0-490c-ac24-ee05105011a7
Pickard, K.
e5188669-dff1-49c7-9c6f-8122b0c74bd9
Bullock, M.D.
1c251c82-7dc6-4df8-9ba2-6b55a4daf947
Jenei, V.
04d82852-7d30-458a-bc0b-f00ae6c5dd52
Strefford, J.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Mitter, R.
dada2010-a5e1-4dd7-8bbd-aa52104f997e
Kelly, G.
4ec853ad-85b1-40c5-8537-2f6f83d852c2
Primrose, J.N.
d85f3b28-24c6-475f-955b-ec457a3f9185
Thomas, G.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Packham, G.K.
fdabe56f-2c58-469c-aadf-38878f233394
Mirnezami, A.H.
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Zhang, L., Pickard, K., Bullock, M.D., Jenei, V., Strefford, J., Mitter, R., Kelly, G., Primrose, J.N., Thomas, G., Packham, G.K. and Mirnezami, A.H.
(2013)
miR-153 supports colorectal cancer progression via pleiotropic effects that enahance invasion and chemotherapeutic resistance.
Cancer Research, 73, .
(doi:10.1158/0008-5472.CAN-12-3308).
(PMID:23950211)
Abstract
Although microRNAs (miRNA) have been broadly studied in cancer, comparatively less is understood about their role in progression. Here we report that miR-153 has a dual role during progression of colorectal cancer by enhancing cellular invasiveness and platinum-based chemotherapy resistance. miRNA profiling revealed that miR-153 was highly expressed in a cellular model of advanced stage colorectal cancer. Its upregulation was also noted in primary human colorectal cancer compared with normal colonic epithelium and in more advanced colorectal cancer stages compared with early stage disease. In colorectal cancer patients followed for 50 months, 21 of 30 patients with high levels of miR-153 had disease progression compared with others in this group with low levels of miR-153. Functional studies revealed that miR-153 upregulation increased colorectal cancer invasiveness and resistance to oxaliplatin and cisplatin both in vitro and in vivo. Mechanistic investigations indicated that miR-153 promoted invasiveness indirectly by inducing matrix metalloprotease enzyme 9 production, whereas drug resistance was mediated directly by inhibiting the Forkhead transcription factor Forkhead box O3a (FOXO3a). In support of the latter finding, we found that levels of miR-153 and FOXO3a were inversely correlated in matched human colorectal cancer specimens. Our findings establish key roles for miR-153 overexpression in colorectal cancer progression, rationalizing therapeutic strategies to target expression of this miRNA for colorectal cancer treatment.
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e-pub ahead of print date: 2013
Published date: 21 October 2013
Organisations:
Cancer Sciences
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Local EPrints ID: 359507
URI: http://eprints.soton.ac.uk/id/eprint/359507
ISSN: 0008-5472
PURE UUID: bde71526-df7b-4830-a657-2b671e15e2d4
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Date deposited: 04 Nov 2013 12:13
Last modified: 15 Mar 2024 03:20
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Author:
L. Zhang
Author:
K. Pickard
Author:
M.D. Bullock
Author:
V. Jenei
Author:
R. Mitter
Author:
G. Kelly
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