Journal Article

MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells

Fan, Daiming, Li, Ling, Ji, Qing, Lawrence, Theodore S., Hao, Xinbao, Zhang, Min, Yang, Meng, Xu, Liang, Tang, Wenhua, Xiang, Debing, DeSano, Jeffrey T., Bommer, Guido T., Fearon, Eric R.

2009

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 3' Untranslated Regions / AC133 Antigen / Androgens / Animals / Antigens, CD - immunology / Apoptosis / Base Sequence / Bcl-2 protein / Brain cancer / Breast cancer / Cancer / CD44 antigen / Cell Biology/Cellular Death and Stress Responses / Cell Biology/Gene Expression / Cell Cycle / Cell death / Cell Division / Cell fate / Cell growth / Cell proliferation / Cell self-renewal / Cell survival / Cells (biology) / Chemotherapy / Development and progression / DNA Primers / Female / Gastroenterology and Hepatology/Gastrointestinal Cancers / Gene expression / Glycoproteins - immunology / Hospitals / Humans / Hyaluronan Receptors - immunology / Inhibition / Internal medicine / Laboratories / Metastasis / Mice / Mice, Nude / MicroRNA / MicroRNAs / MicroRNAs - physiology / miRNA / Notch protein / Notch1 protein / Oncology / Oncology/Gastrointestinal Cancers / p53 Protein / Pancreatic cancer / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - pathology / Pathology/Pathophysiology / Peptides - immunology / Prostate cancer / Proteins / Radiation / Restoration / Reverse Transcriptase Polymerase Chain Reaction / Ribonucleic acid / RNA / Stem cells / Transcription / Transcription (Genetics) / Transfection / Tumor cell lines / Tumor proteins / Tumors