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Nat Commun. 2015 Apr 15;6:6879. doi: 10.1038/ncomms7879.

miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β.

Author information

1
1] School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA [2] Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA.
2
Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, USA.
3
School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA.
4
1] Departments of Medicine, Genetic Medicine and Surgery, Weill Cornell Medical College, New York, New York 10021, USA [2] Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York 10021, USA.
5
1] Department of Clinical Sciences, University of Barcelona, Barcelona 08193, Spain [2] Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, CIBERESP, Barcelona E08907, Spain.
6
Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA.
7
Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, North Carolina 27710, USA.
8
Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853, USA.
9
Departments of Medicine, Genetic Medicine and Surgery, Weill Cornell Medical College, New York, New York 10021, USA.
10
1] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10065, USA [2] Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10065, USA.
11
1] School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA [2] Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA [3] Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, USA.

Abstract

As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-β signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-β activates miR-1269 via Sox4, while miR-1269a enhances TGF-β signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis.

PMID:
25872451
PMCID:
PMC4399006
DOI:
10.1038/ncomms7879
[Indexed for MEDLINE]
Free PMC Article

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