MicroRNA miR-34 Inhibits Human Pancreatic Cancer

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Abstract9 Y1 O7 p3 g- H( T
Background: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect
: O. d6 ?: u+ U# o8 G/ x3 G& Q0 xexpression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34
7 q- L3 a! w! U9 gfamily members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are) v8 i2 P- D/ O0 Q( R5 R/ S
Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer% p2 C: q% H: H
stem cells.
* o, }" I/ i7 K* L, CMethodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines% R6 D5 Y& r* Z  l9 l/ j$ T
MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the& L4 m6 K5 n# ]4 c, l, r
pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-27 b3 D- G  ~' Z+ @
and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and
( K; A1 u( e% \# g$ qG2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+9 p+ @, {7 v. l: F9 r
MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high7 ~8 l0 r; b  A9 N- ~
levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating' T3 F. R0 A* _  B7 j
cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.3 x4 L3 w3 L: w
Conclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function( L$ X/ c* D; C
of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in
! j8 c/ Z5 T9 D' Q4 `+ B) Mpancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,9 M# j6 Q) Z7 I8 `! ^
implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.+ h4 q- P5 _2 f, ]8 A% o2 ]9 k
Restoration of miR-34 may hold significant promise as a novel molec

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