Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-03962-x
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Funding
- Action Against Cancer (AAC)
- Pancreatic Cancer UK (PCUK)
- Academy of Medical Sciences
- Royal College of Surgeons of Edinburgh
- Colin McDavid Family Trust
- No Surrender Cancer Trust
- Ralph Bates Pancreatic Cancer Research Fund
- Dutch Cancer Society, KWF [10401]
- Italian Association for Cancer Research AIRC/Start-Up grant
- Istituto Toscano Tumouri ITT-grant
- Regione Toscana Progetto DIAMANTE/FAS grant
- Medical Research Council [MR/L01632X/1]
- MRC [MR/L01632X/1] Funding Source: UKRI
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TGF-beta/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-beta 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-beta also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR125b or miR-100 affects the TGF-beta-mediated response indicating that these miRNAs are important TGF-beta 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-beta induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.
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