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MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells
BACKGROUND: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729376/ https://www.ncbi.nlm.nih.gov/pubmed/19714243 http://dx.doi.org/10.1371/journal.pone.0006816 |
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author | Ji, Qing Hao, Xinbao Zhang, Min Tang, Wenhua Yang, Meng Li, Ling Xiang, Debing DeSano, Jeffrey T. Bommer, Guido T. Fan, Daiming Fearon, Eric R. Lawrence, Theodore S. Xu, Liang |
author_facet | Ji, Qing Hao, Xinbao Zhang, Min Tang, Wenhua Yang, Meng Li, Ling Xiang, Debing DeSano, Jeffrey T. Bommer, Guido T. Fan, Daiming Fearon, Eric R. Lawrence, Theodore S. Xu, Liang |
author_sort | Ji, Qing |
collection | PubMed |
description | BACKGROUND: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells. METHODOLOGY/PRINCIPAL FINDINGS: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+ MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53–miR34, potentially via inhibiting pancreatic cancer stem cells. |
format | Text |
id | pubmed-2729376 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-27293762009-08-28 MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells Ji, Qing Hao, Xinbao Zhang, Min Tang, Wenhua Yang, Meng Li, Ling Xiang, Debing DeSano, Jeffrey T. Bommer, Guido T. Fan, Daiming Fearon, Eric R. Lawrence, Theodore S. Xu, Liang PLoS One Research Article BACKGROUND: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells. METHODOLOGY/PRINCIPAL FINDINGS: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+ MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53–miR34, potentially via inhibiting pancreatic cancer stem cells. Public Library of Science 2009-08-28 /pmc/articles/PMC2729376/ /pubmed/19714243 http://dx.doi.org/10.1371/journal.pone.0006816 Text en Ji et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Ji, Qing Hao, Xinbao Zhang, Min Tang, Wenhua Yang, Meng Li, Ling Xiang, Debing DeSano, Jeffrey T. Bommer, Guido T. Fan, Daiming Fearon, Eric R. Lawrence, Theodore S. Xu, Liang MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells |
title | MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells |
title_full | MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells |
title_fullStr | MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells |
title_full_unstemmed | MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells |
title_short | MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells |
title_sort | microrna mir-34 inhibits human pancreatic cancer tumor-initiating cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729376/ https://www.ncbi.nlm.nih.gov/pubmed/19714243 http://dx.doi.org/10.1371/journal.pone.0006816 |
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