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Zhao, Y.* ; Zhao, L.* ; Ischenko, I.* ; Bao, Q.* ; Schwarz, B.E.* ; Nieß, H.* ; Wang, Y.* ; Renner, A.* ; Mysliwietz, J. ; Jauch, K.-W.* ; Nelson, P.J.* ; Ellwart, J.W. ; Bruns, C.J.* ; Camaj, P.*

Antisense inhibition of microRNA-21 and microRNA-221 in tumor-initiating stem-like cells modulates tumorigenesis, metastasis, and chemotherapy resistance in pancreatic cancer.

Target. Oncol. 10, 535-548 (2015)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
Our preliminary studies identified a small population side population (SP) cells in pancreatic cancer cells with stem cell-like properties, which were able to induce fast and aggressive tumor formation in nude mice. Gene expression analysis showed a significant difference in the expression of more than 1,300 genes in SP cells, among which a highly significant difference in microRNA expression of miR-21 and miR-221 between SP and NSP cells was identified. SP cells were identified and characterized by flow cytometry using Hoechst 33342 dye staining from a highly metastatic human pancreatic cancer cell line (L3.6pl). Antagomir transfection was performed using miRNA-21 and miRNA-221 antisense oligonucleotides (ASOs) and followed by detection of cell apoptosis, cell cycle progression, chemosensitivity, and invasion. Sorted SP cells from gemcitabine-resistant L3.6pl cells (L3.6plGres-SP) cells were orthotopically implanted in nude mice with or without miRNA-21 and miRNA-221 ASOs mono- and combination therapy. The administration of antagomir-21 and antagomir-221 significantly reduced the SP cell fraction, decreased SP cell differentiation, and downstream gene regulation, and thereby induced reduction of L3.6pl cell proliferation, invasion, and chemoresistance against gemcitabine and 5-Fluorouracil. Combination of ASOs therapy against miRNA-21 and miRNA-221 significantly inhibited primary tumor growth and metastasis compared to single antagomir treatment, especially, in L3.6plGres-SP-induced pancreatic tumor growth in vivo. These findings further indicate that the inhibition of miR-21 and miR-221 appear particularly suitable to target stem-like subpopulations and address their specific biological function to promote tumor progression in pancreatic cancer.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Chemotherapy Resistance ; Metastasis ; Mirnas ; Pancreatic Cancer ; Side Population ; Tumorigenesis
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 1776-2596
e-ISSN 1776-260X
Journal Targeted Oncology
Quellenangaben Volume: 10, Issue: 4, Pages: 535-548 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Paris
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-501793-001
DOI 10.1007/s11523-015-0360-2
WOS ID WOS:000365770300008
Scopus ID 84949097148
Scopus ID 84921993802
Erfassungsdatum 2015-02-08
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