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

Antisense inhibition of microRNA-21 and microRNA-221 in tumor-initiating stem-like cells... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Targeted Oncology Springer Journals

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

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References (50)

Publisher
Springer Journals
Copyright
Copyright © 2015 by Springer International Publishing Switzerland
Subject
Medicine & Public Health; Oncology; Biomedicine general
ISSN
1776-2596
eISSN
1776-260X
DOI
10.1007/s11523-015-0360-2
pmid
25639539
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

Targeted Oncology – Springer Journals

Published: Feb 3, 2015

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