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 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.


RESULTS
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
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.
Ji
Qing
Q
Department of Radiation Oncolog, University of Michigan, Ann Arbor, Michigan, United States of America.
Hao
Xinbao
X
Zhang
Min
M
Tang
Wenhua
W
Yang
Meng
M
Li
Ling
L
Xiang
Debing
D
Desano
Jeffrey T
JT
Bommer
Guido T
GT
Fan
Daiming
D
Fearon
Eric R
ER
Lawrence
Theodore S
TS
Xu
Liang
L
D020413:3' Untranslated Regions; D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis; D001483:Base Sequence; D002453:Cell Cycle; D002455:Cell Division; D017931:DNA Primers; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology*; D010455:Peptides / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020413:3' Untranslated Regions; D000071916:AC133 Antigen; D015703:Antigens, CD; D017931:DNA Primers; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D035683:MicroRNAs; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse