MicroRNA miR-34 Inhibits Human Pancreatic Cancer

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Abstract
3 p; u% `' l' A, w: dBackground: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect
! v9 x7 t3 K6 ]4 P; l  ?expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34* n9 O+ R5 X3 c# Z3 D
family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are* k; z5 y! _8 M
Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer. @0 N4 x6 k& J7 C) u9 Z) v
stem cells.
2 d+ q. Q0 n* h8 t0 F% {/ y7 [' rMethodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines
* i& _; m- ~, f+ w4 `MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the
# H! e* ]( ]' D. |. Lpancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2
7 O0 w% x8 {8 iand Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and# N9 X3 V5 ]/ z6 n
G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+
6 J" |9 X& l$ D5 F& ]MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high
% p4 {0 J& y/ y3 Z7 ~levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating! \, t" B! m% n
cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.8 h# |2 t9 {& u/ i  m
Conclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function
9 R4 d4 B8 y+ O$ tof the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in3 {! X; O: \! l! p: Y
pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,$ f' o! i3 F3 a2 O! W8 y
implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.! B: k3 t1 x5 Z$ D$ Y
Restoration of miR-34 may hold significant promise as a novel molec

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