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

Autor:	Ottaviani S; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK., Stebbing J; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK., Frampton AE; Department of Surgery and Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital Campus, London, W12 0HS, UK.; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Institute of Reproductive and Developmental Biology (IRDB), London, W12 0NN, UK., Zagorac S; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK., Krell J; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Institute of Reproductive and Developmental Biology (IRDB), London, W12 0NN, UK., de Giorgio A; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK., Trabulo SM; Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, 28028, Spain.; Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK., Nguyen VTM; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK., Magnani L; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK., Feng H; Epigenetics and Genome Stability Team, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK., Giovannetti E; Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, 1081 HV, The Netherlands.; Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, 56126, Italy., Funel N; Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, 56126, Italy., Gress TM; Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, 35037, Germany., Jiao LR; Department of Surgery and Cancer, HPB Surgical Unit, Imperial College, Hammersmith Hospital Campus, London, W12 0HS, UK., Lombardo Y; Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK., Lemoine NR; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK., Heeschen C; Stem Cells & Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, 28028, Spain.; Stem Cells in Cancer & Ageing, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK., Castellano L; 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.; University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, BN1 9QG, UK. l.castellano@sussex.ac.uk.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 May 10; Vol. 9 (1), pp. 1845. Date of Electronic Publication: 2018 May 10.
DOI:	10.1038/s41467-018-03962-x
Abstrakt:	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.
Databáze:	MEDLINE
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