2026-06-14T05:05:28Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/52572024-09-27T10:05:17Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19607
Repisalud
author
Cioffi, Michele
author
Trabulo, Sara M.
author
Sanchez-Ripoll, Yolanda
author
Miranda-Lorenzo, Irene
author
Lonardo, Enza
author
Dorado, Jorge
author
Reis Vieira, Catarina
author
Ramirez, Juan Carlos
author
Hidalgo, Manuel
author
Aicher, Alexandra
author
Hahn, Stephan
author
Sainz, Jr., Bruno
author
Heeschen, Christopher
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Unión Europea. Comisión Europea
funder
Ministerio de Economía y Competitividad (España)
funder
Instituto de Salud Carlos III
funder
Fundación La Caixa
2017-10-30T13:32:28Z
2017-10-30T13:32:28Z
2015
Gut. 2015; 64(12):1936-48
10.1136/gutjnl-2014-308470
1468-3288
0017-5749
Gut
25887381
http://hdl.handle.net/20.500.12105/5257
Objective Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes. Design Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs. Results We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-beta 1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer. Conclusions Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.
eng
SELF-RENEWAL
DOWNSTREAM TARGET
MICRORNA CLUSTER
SOLID TUMORS
TBX3
PATHWAY
EXPRESSION
TUMORIGENICITY
IDENTIFICATION
PROLIFERATION
The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells
journal article
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TheMiR-17-92ClusterCounteracts_2015.pdf
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0e4f47e531fefcaa9b7f4f1e5bfd249c
57029
text/plain
TheMiR-17-92ClusterCounteracts_2015.pdf.txt