MicroRNA miR-34 Inhibits Human Pancreatic Cancer

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Abstract& X9 f: `- P9 y7 x0 q7 r1 I
Background: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect
" ?* ?. r3 ]/ x/ `& o  hexpression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34
6 a4 [0 q9 I/ @+ O* I) U' zfamily members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are% d+ @" f0 D6 D0 e; ~
Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer
& m& j& F& V2 G$ q8 Pstem cells.* ?5 i$ x1 G4 l
Methodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines
) J9 `3 g( A* q' ~. pMiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the5 t8 H! g8 L* `3 G8 m! G* _! M. e! ^
pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2
& s3 C: A* [9 L5 xand Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and
6 ~0 {: V3 G! ~7 sG2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+
3 i6 `0 \' h; w: g. YMiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high
" [, @; f6 x+ K3 Q1 wlevels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating
/ a8 _! A! X# c* l+ Wcell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.
( y, T0 l6 J0 [/ V2 LConclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function
; w5 `" _" ^3 q4 j# ^of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in
9 r0 }2 ^$ {  N; N+ w1 T* Tpancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,
, q% M0 T' U- n* q7 l4 kimplying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.+ G) v# \( g7 D: _* s' n, W
Restoration of miR-34 may hold significant promise as a novel molec

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