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

Pengcheng Bu, Lihua Wang, Kai Yuan Chen, Nikolai Rakhilin, Jian Sun, Adria Closa, Kuei Ling Tung, Sarah King, Anastasia Kristine Varanko, Yitian Xu, Joyce Huan Chen, Amelia S. Zessin, James Shealy, Bethany Cummings, David Hsu, Steven M. Lipkin, Victor Moreno, Zeynep H. Gümüş, Xiling Shen

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

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.

Original languageEnglish
Article number6879
JournalNature Communications
Volume6
DOIs
StatePublished - 15 Apr 2015

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