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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

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

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. More... »

PAGES

1845

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41467-018-03962-x

DOI

http://dx.doi.org/10.1038/s41467-018-03962-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1103817392

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29748571


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