MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells

PLoS One. 2009 Aug 28;4(8):e6816. doi: 10.1371/journal.pone.0006816.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • AC133 Antigen
  • Animals
  • Antigens, CD / immunology
  • Apoptosis
  • Base Sequence
  • Cell Cycle
  • Cell Division
  • DNA Primers
  • Female
  • Glycoproteins / immunology
  • Humans
  • Hyaluronan Receptors / immunology
  • Mice
  • Mice, Nude
  • MicroRNAs / physiology*
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology*
  • Peptides / immunology
  • Reverse Transcriptase Polymerase Chain Reaction


  • 3' Untranslated Regions
  • AC133 Antigen
  • Antigens, CD
  • DNA Primers
  • Glycoproteins
  • Hyaluronan Receptors
  • MicroRNAs
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse