MicroRNA miR-34 Inhibits Human Pancreatic Cancer

jiays

Abstract
( _' b2 V3 h- g) Y) l. XBackground: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect
3 f% S6 x' F8 {" T4 Cexpression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34
, N+ _. g4 y  N9 N* Ofamily members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are0 ]9 C: `& N5 g' ^2 O, d2 n- ]
Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer
/ W4 s  V! w4 Tstem cells.6 w7 z; Q! [/ N5 D2 I6 H7 c
Methodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines
2 g; ~( [3 u2 _% RMiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the' s: Y# H% ]1 O
pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2* e& G& G5 C& C+ ?- J
and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and1 V4 ^% b* k9 a* Z
G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+. x% }, y1 A. m0 h* B- ^
MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high
5 L5 T. g4 m  i  @levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating; O2 v8 m' V2 }# N  t) ~  E
cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.
3 M; \  Y2 `3 B: `, G! R$ k$ g& c% ^Conclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function7 c! j0 j: d1 a/ }: d# x  d
of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in$ l7 \. x6 R3 t! @+ A7 q, z- @, `5 s
pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,
; {5 h+ b! \. u* L1 Vimplying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.$ o( d4 {* Y& O8 H
Restoration of miR-34 may hold significant promise as a novel molec

fjmedzengyue

学习