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

Silvia Ottaviani, Justin Stebbing, Adam E. Frampton, Sladjana Zagorac, Jonathan Krell, Alexander de Giorgio, Sara M. Trabulo, Nguyen Van T. M., Luca Magnani, Hugang Feng, Elisa Giovannetti, Niccola Funel, Thomas M. Gress, Long R. Jiao, Ylenia Lombardo, Nicholas R. Lemoine, Christopher Heeschen and Leandro Castellano ()
Additional contact information
Silvia Ottaviani: Imperial Centre for Translational and Experimental Medicine (ICTEM)
Justin Stebbing: Imperial Centre for Translational and Experimental Medicine (ICTEM)
Adam E. Frampton: Hammersmith Hospital Campus
Sladjana Zagorac: Imperial Centre for Translational and Experimental Medicine (ICTEM)
Jonathan Krell: Institute of Reproductive and Developmental Biology (IRDB)
Alexander de Giorgio: Imperial Centre for Translational and Experimental Medicine (ICTEM)
Sara M. Trabulo: Spanish National Cancer Research Centre (CNIO)
Nguyen Van T. M.: Imperial Centre for Translational and Experimental Medicine (ICTEM)
Luca Magnani: Imperial Centre for Translational and Experimental Medicine (ICTEM)
Hugang Feng: The Institute of Cancer Research
Elisa Giovannetti: Cancer Center Amsterdam
Niccola Funel: AIRC Start-Up Unit, University of Pisa
Thomas M. Gress: Philipps-University Marburg
Long R. Jiao: Hammersmith Hospital Campus
Ylenia Lombardo: Imperial Centre for Translational and Experimental Medicine (ICTEM)
Nicholas R. Lemoine: Queen Mary University of London
Christopher Heeschen: Spanish National Cancer Research Centre (CNIO)
Leandro Castellano: Imperial Centre for Translational and Experimental Medicine (ICTEM)

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03962-x

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