MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells
By Qing Ji, Xinbao Hao, Wenhua Tang, Meng Yang, Ling Li, Debing Xiang, Jeffrey Desano, G. Bommer, D. Fan, Eric R. Fearon and 2 more. PLoS ONE, 2009
735 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Molecular Biology, Rheumatology
View Paper: https://www.semanticscholar.org/paper/66bf4852169f5882efc60914255377e2331e5740
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Citations in the corpus
- MicroRNAs in development and disease. (2011, background): “This was associated with downregulation of its targets Bcl-2, notch-1, and notch-2 proteins, apoptosis, cell cycle arrest, and reduced invasion (274).”
- Identification of miR-34a as a potent inhibitor of prostate cancer progenitor cells and metastasis by directly repressing CD44 (2011, neutral): “The emerging role of miR-34a in regulating other CS”
- Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34 (2010, background): “miR-34a also inhibits the growth of pancreatic cancer stem cells (17).”
- Microvesicles Derived from Adult Human Bone Marrow and Tissue Specific Mesenchymal Stem Cells Shuttle Selected Pattern of miRNAs (2010, background): “In particular, the following target proteins were downregulated: PTEN which is known to be targeted by miR-21 [28,29], cyclin D1 which is known to be targeted by miR-100, miR-99a and miR-223 [30] and Bcl-2 which is known to be targeted directly by miR-34, miR-181b and miR16 [31,32,33] or indirectly ”