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dc.date.accessioned2018-06-05T10:20:14Z
dc.date.issued2018-05en_US
dc.identifierhttps://www.nature.com/articles/s41467-018-03962-xen_US
dc.identifier.citationNATURE COMMUNICATIONS, 2018, 9en_US
dc.identifier.issn2041-1723en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1708
dc.description.abstractTGF-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.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectcancer stem-cells pancreatic tumor-growth mesenchymal transition laser microdissection self-renewal expression micrornas target adenocarcinoma biogenesis Science & Technology - Other Topicsen_US
dc.titleTGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progressionen_US
dc.typeJournal Article
rioxxterms.licenseref.startdate2018-05en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfNATURE COMMUNICATIONSen_US
pubs.notesISI Document Delivery No.: GF2LM Times Cited: 0 Cited Reference Count: 54 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, Niccola Gress, Thomas M. Jiao, Long R. Lombardo, Ylenia Lemoine, Nicholas R. Heeschen, Christopher Castellano, Leandro 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] The authors thank Action Against Cancer (AAC), Pancreatic Cancer UK (PCUK), The Academy of Medical Sciences, The Royal College of Surgeons of Edinburgh, The Colin McDavid Family Trust, No Surrender Cancer Trust (in memory of Jason Boas), Mr Alessandro Dusi, Cheryl Whitehead, BHM, Sir Douglas Myers, and The Ralph Bates Pancreatic Cancer Research Fund for funding this study. Financial support was provided by the Dutch Cancer Society, KWF# 10401 grant to E.G., Italian Association for Cancer Research AIRC/Start-Up grant to E.G., Istituto Toscano Tumouri ITT-grant to N.F. and E.G., and the Regione Toscana "Progetto DIAMANTE"/FAS grant to N.F. and E.G. The authors thank Prof. Matthias Lohr and Dr Rainer Heuchel at Karolinska University Hospital, Stockholm, Sweden, for providing the TGF-beta 1 and empty vector expressing PANC-1 cells. This work used the computing resources of the UK MEDical BIOinformatics partnership-aggregation, integration, visualization, and analysis of large, complex data (UK MED-BIO) which is supported by the Medical Research Council [grant number MR/L01632X/1]. 0 Nature publishing group Londonen_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Epigenetics and Genome Stability
pubs.volume9en_US
pubs.embargo.termsNot knownen_US
pubs.oa-locationhttps://www.nature.com/articles/s41467-018-03962-x.pdfen_US
icr.researchteamEpigenetics and Genome Stabilityen_US
dc.contributor.icrauthorFeng, Hugangen_US


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