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MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity.

Authors :
Giovannetti E
Funel N
Peters GJ
Del Chiaro M
Erozenci LA
Vasile E
Leon LG
Pollina LE
Groen A
Falcone A
Danesi R
Campani D
Verheul HM
Boggi U
Source :
Cancer research [Cancer Res] 2010 Jun 01; Vol. 70 (11), pp. 4528-38. Date of Electronic Publication: 2010 May 11.
Publication Year :
2010

Abstract

MicroRNA-21 (miR-21) was reported to be overexpressed and contributes to invasion and gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to evaluate whether miR-21 expression was associated with the overall survival (OS) of PDAC patients treated with gemcitabine and to provide mechanistic insights for new therapeutic targets. miR-21 expression was evaluated in cells (including 7 PDAC cell lines, 7 primary cultures, fibroblasts, and a normal pancreatic ductal cell line) and tissues (neoplastic specimens from 81 PDAC patients and normal ductal samples) isolated by laser microdissection. The role of miR-21 on the pharmacologic effects of gemcitabine was studied with a specific miR-21 precursor (pre-miR-21). Patients with high miR-21 expression had a significantly shorter OS both in the metastatic and in the adjuvant setting. Multivariate analysis confirmed the prognostic significance of miR-21. miR-21 expression in primary cultures correlated with expression in their respective tissues and with gemcitabine resistance. Pre-miR-21 transfection significantly decreased antiproliferative effects and apoptosis induction by gemcitabine, whereas matrix metalloproteinase (MMP)-2/MMP-9 and vascular endothelial growth factor expression were upregulated. Addition of inhibitors of phosphoinositide 3-kinase and mammalian target of rapamycin resulted in decrease of phospho-Akt and prevented pre-miR-21-induced resistance to the proapoptotic effects of gemcitabine. miR-21 expression correlated with outcome in PDAC patients treated with gemcitabine. Modulation of apoptosis, Akt phosphorylation, and expression of genes involved in invasive behavior may contribute to the role of miR-21 in gemcitabine chemoresistance and to the rational development of new targeted combinations.<br /> (Copyright 2010 AACR.)

Details

Language :
English
ISSN :
1538-7445
Volume :
70
Issue :
11
Database :
MEDLINE
Journal :
Cancer research
Publication Type :
Academic Journal
Accession number :
20460539
Full Text :
https://doi.org/10.1158/0008-5472.CAN-09-4467