CNIO
Permanent URI for this community
Browse
Browsing CNIO by Funding agency "Action Against Cancer"
Now showing 1 - 1 of 1
Results Per Page
Sort Options
Publication TGF-β induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression(Nature Publishing Group, 2018-05-10) Ottaviani, Silvia; Stebbing, Justin; Frampton, Adam E; Zagorac, Sladjana; Krell, Jonathan; de Giorgio, Alexander; Trabulo, Sara M; Nguyen, Van T M; Magnani, Luca; Feng, Hugang; Giovannetti, Elisa; Funel, Niccola; Gress, Thomas M; Jiao, Long R; Lombardo, Ylenia; Lemoine, Nicholas R; Heeschen, Christopher; Castellano, Leandro; Action Against Cancer; Pancreatic Cancer UK; Academy of Medical Sciences (Reino Unido); Royal College of Surgeons of Edinburgh; Colin McDavid Family Trust; No Surrender Cancer Trust; Ralph Bates Pancreatic Cancer Research Fund; Dutch Cancer Society (Holanda); Italian Association for Cancer Research; Tumour Institute of Tuscany (Italia); Regione Toscana "Progetto DIAMANTE"/FAS grant; Medical Research Council (Reino Unido)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.