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Nat Commun. 2018 May 10;9(1):1845. doi: 10.1038/s41467-018-03962-x.

TGF-β induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression.

Author information

1
Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK.
2
Department of Surgery and Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital Campus, London, W12 0HS, UK.
3
Department of Surgery and Cancer, Division of Cancer, Imperial College London, Institute of Reproductive and Developmental Biology (IRDB), London, W12 0NN, UK.
4
Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, 28028, Spain.
5
Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
6
Epigenetics and Genome Stability Team, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
7
Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, 1081 HV, The Netherlands.
8
Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, 56126, Italy.
9
Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, 35037, Germany.
10
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
11
Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK. l.castellano@sussex.ac.uk.
12
University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, BN1 9QG, UK. l.castellano@sussex.ac.uk.

Abstract

TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions' pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.

PMID:
29748571
PMCID:
PMC5945639
DOI:
10.1038/s41467-018-03962-x
[Indexed for MEDLINE]
Free PMC Article

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