s41467-018-03962-x.pdf (3.78 MB)
TGF-ß induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression.
journal contribution
posted on 2023-06-09, 13:43 authored by 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, Nicola Funel, Thomas Gress, Long Jiao, Ylenia Lombardo, Nicholas R Lemoine, Christopher Heeschen, Leandro CastellanoLeandro CastellanoAbstract TGF-ß/Activin induces epithelial-to-mesenchymal transition (EMT) and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-ß 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-ß also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-ß-mediated response indicating that these miRNAs are important TGF-ß effectors. We integrated 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-ß induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b, play opposing roles in controlling PDAC tumourigenesis.
History
Publication status
- Published
File Version
- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Nature Publishing GroupExternal DOI
Issue
1845Volume
9Page range
1-18Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Gene Expression Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-06-13First Open Access (FOA) Date
2018-06-13First Compliant Deposit (FCD) Date
2018-06-12Usage metrics
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