MicroRNA miR-34 Inhibits Human Pancreatic Cancer

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Abstract
- S( `! `6 }" k" XBackground: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect6 _" v9 Q) d( [1 Q4 y
expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34
7 t( T4 v& p/ ~8 \family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are6 o, h- Z4 [" D
Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer1 y1 L0 e5 }5 p% ?& A
stem cells.
) w& h* p  H1 S1 K. rMethodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines0 `6 q" w1 n% W, d7 t. q
MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the2 U, L9 o2 C7 z* C4 x* ~
pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2( Y* x3 z; a4 R
and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and
2 [- e7 t8 c# T1 J( A; Y/ SG2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+2 O6 l9 Z) R* J+ T3 Q5 W
MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high
/ j) l4 Z# _) y0 |levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating
4 D9 R! E4 N; M2 V5 jcell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.2 |- _& I9 V+ z1 P7 F
Conclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function
2 }( N! U, w' d$ [3 C5 ^( mof the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in
: H9 q" }5 n( e# s! ?+ x  q7 M$ |1 X( Dpancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,3 C7 R4 H+ S- T# l" Y
implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.
; @& N9 L6 a5 H' I7 V: ^Restoration of miR-34 may hold significant promise as a novel molec

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