MicroRNA miR-34 Inhibits Human Pancreatic Cancer

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Abstract5 y1 {$ j; j0 E
Background: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect
9 `1 R' G- r5 W$ c4 k& kexpression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34# |& w9 e1 \) l% H& _3 d: H  T: W
family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are
0 b5 @1 t5 Y' I  lNotch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer; f( `9 s* p+ C' A0 H
stem cells.
2 l% ?8 s' ^, o. @. o# g- X/ JMethodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines
  X$ q1 d3 L* u5 z, p2 h& P5 YMiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the
3 V" v2 _- e2 j; {pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2% H' t  Q2 ?! h2 _% E
and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and
4 u0 x0 |1 e- y/ f, E9 }G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+
; \' _7 t- g1 g' lMiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high
" c, l, U! ^+ ?: x/ `4 O8 p! ~6 \levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating+ y0 h! b! q  }& Q" A1 ]1 A. i
cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.& F% i: P; q& S/ ^- G' f6 b/ }4 g* U
Conclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function
  X% U- P* ~) M0 Pof the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in6 j: K! I3 c4 f( L) f- r
pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,
3 K1 Y9 _) V) \. Y5 _implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.
" g! x- s$ Z' ?+ }5 x* hRestoration of miR-34 may hold significant promise as a novel molec

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