MicroRNA miR-34 Inhibits Human Pancreatic Cancer

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Abstract
. h9 P/ R/ h2 W# o( hBackground: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect
5 r; U# I/ J9 ^( W, a# Zexpression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34
1 ~# v( A7 E' xfamily members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are
; d. O) f/ y: E3 |9 j- P2 T0 mNotch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer  \, O' H3 U" ]
stem cells.
5 }5 @. r" u7 e  h3 N* O: Z# @9 VMethodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines( g& w7 X7 U- n. c$ b
MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the. m/ ^, H/ t, r) Q$ K# p$ ~
pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2; b: m/ _/ X0 `0 I* k. I: o
and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and
0 S/ Q; L- e* [G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+
& b+ Q/ |. H& Z& G1 aMiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high' e, t7 i0 l' h( ~
levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating
* `1 ?7 @* I3 ccell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.9 V  ~9 [8 g; l6 z0 `0 I) d  b
Conclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function
. {. A. z5 q: y& I5 w  Gof the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in/ h6 z2 F# n5 y+ D4 d
pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,) P0 |+ I  Q3 r; `
implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.
; t" y, \# I, G9 y( ~- GRestoration of miR-34 may hold significant promise as a novel molec

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