TY - JOUR
T1 - TGF-β induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression
AU - Ottaviani, Silvia
AU - Stebbing, Justin
AU - Frampton, Adam E.
AU - Zagorac, Sladjana
AU - Krell, Jonathan
AU - de Giorgio, Alexander
AU - Trabulo, Sara M.
AU - Nguyen, Van T. M.
AU - Magnani, Luca
AU - Feng, Hugang
AU - Giovannetti, Elisa
AU - Funel, Niccola
AU - Gress, Thomas M.
AU - Jiao, Long R.
AU - Lombardo, Ylenia
AU - Lemoine, Nicholas R.
AU - Heeschen, Christopher
AU - Castellano, Leandro
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85047062735&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29748571
U2 - https://doi.org/10.1038/s41467-018-03962-x
DO - https://doi.org/10.1038/s41467-018-03962-x
M3 - Article
C2 - 29748571
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1845
ER -