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, Van T. M. Nguyen, Luca Magnani, Hugang Feng, Elisa Giovannetti, Niccola Funel, Thomas M. Gress, Long R. Jiao, Ylenia Lombardo, Nicholas R. Lemoine, Christopher Heeschen, Leandro Castellano

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article number1845
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018

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