MicroRNA miR-34 Inhibits Human Pancreatic Cancer

jiays

Abstract
! F# W8 v( n; q" t8 eBackground: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect; h2 B6 X8 ~$ K6 y+ u
expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34
1 S: W9 x" `$ ~: ]# D* [5 ?+ lfamily members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are
+ x8 Z- t4 ^6 n4 hNotch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer8 R8 L; _# x. I# e5 m7 s4 b6 N) ^
stem cells.
+ l6 a% J% c; b: _' Y( CMethodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines7 Z" p' r. u7 g7 o3 k& A9 p
MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the
. r9 s9 ~5 P0 z4 N9 [2 Fpancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2
/ u8 q7 z8 @0 yand Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and) I# A$ N5 F9 y# x/ C7 v9 @9 ]
G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+
2 z2 Z# C$ x' z7 l5 G3 H+ m& KMiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high
1 }5 r, P8 x) Q% n. {levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating7 ]9 u1 o9 M3 Y8 O/ v4 @
cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.
0 ~: e4 |0 l  Y4 T1 a2 [Conclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function
8 m( E; g3 U$ Nof the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in
" E  P- ?. D. I6 }. a; D7 zpancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,/ O* @' B# c4 q( Y) T) K% f
implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.4 \& v( F& R8 D$ F% }7 Y9 Z
Restoration of miR-34 may hold significant promise as a novel molec

fjmedzengyue

学习