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

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Title: TGF-ß induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression
Authors: Ottaviani, S
Stebbing, J
Frampton, A
Zagorac, S
Krell, J
De Giorgio, AJR
Trabulo, S
Nguyen, V
Magnani, L
Feng, H
Giovannetti, E
Funel, N
Gress, T
Jiao, LR
Lombardo, Y
Lemoine, NR
Heeschen, C
Castellano, L
Item Type: Journal Article
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 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-ß induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b, play opposing roles in controlling PDAC tumourigenesis.
Issue Date: 10-May-2018
Date of Acceptance: 21-Feb-2018
URI: http://hdl.handle.net/10044/1/57718
DOI: https://dx.doi.org/10.1038/s41467-018-03962-x
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 9
Copyright Statement: © 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/
Sponsor/Funder: Royal College of Surgeons Edinburgh
The Academy of Medical Sciences
Action Against Cancer
Imperial College London
Pancreatic Cancer UK
Cancer Research UK
Imperial College Trust
Funder's Grant Number: SRG/11/048
Junior research Fellowship 2012/2013
Keywords: MD Multidisciplinary
Publication Status: Published
Article Number: ARTN 1845
Appears in Collections:Department of Surgery and Cancer