MicroRNA miR-34 Inhibits Human Pancreatic Cancer

jiays

Abstract! i. `# M/ a+ ?
Background: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect) E$ ]3 U1 K+ P; S0 v7 N, L1 M
expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34
8 i( a: j5 y! kfamily members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are/ @" q. i/ ~, g
Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer
5 L' h+ W0 i2 ~- Q* @; |stem cells./ Z# R; Z% N7 z5 `. o% d  r
Methodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines
: }6 u: }' ?. MMiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the! T: e" z: m, A8 r" O( {" t- F
pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-20 t& e) \, m2 v& K; _9 G: v
and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and
! k. f8 Y( w( N( zG2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+
3 d# ?' M6 q1 [9 N( @$ ]MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high8 U7 X9 p6 F* u" N+ C) c
levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating7 j6 W4 E: }- [' U1 b& h
cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.
  G% H2 }7 o* I5 rConclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function* R  N) J$ |/ o4 b! Z, d
of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in# p/ F" r4 F& l) X- x0 s  {; ]
pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,9 t/ j1 n2 @& P8 Y" w- E' I5 ]
implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.
, _( z' H2 L, L9 E0 zRestoration of miR-34 may hold significant promise as a novel molec

fjmedzengyue

学习