TGF-ß induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression.

Ottaviani, Silvia, Stebbing, Justin, Frampton, Adam E, Zagorac, Sladjana, Krell, Jonathan, de Giorgio, Alexander, Trabulo, Sara M, Nguyen, Van T M, Magnani, Luca, Feng, Hugang, Giovannetti, Elisa, Funel, Nicola, Gress, Thomas, Jiao, Long, Lombardo, Ylenia, Lemoine, Nicholas R, Heeschen, Christopher and Castellano, Leandro (2018) TGF-ß induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression. Nature Communications, 9 (1845). pp. 1-18. ISSN 2041-1723

[img] PDF - Published Version
Available under License Creative Commons Attribution.

Download (3MB)

Abstract

Abstract
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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Research Centres and Groups: Gene Expression Research Group
Subjects: Q Science > Q Science (General) > Q0179.9 Research > Q0180.55 Special topics, A-Z > Q0180.55.M3 Management
Depositing User: Leandro Castellano
Date Deposited: 13 Jun 2018 11:40
Last Modified: 13 Jun 2018 11:40
URI: http://srodev.sussex.ac.uk/id/eprint/76468

View download statistics for this item

📧 Request an update