MicroRNA miR-34 Inhibits Human Pancreatic Cancer

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Abstract7 d2 D2 M+ H  t# {& h, U
Background: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect6 {8 B9 Y$ }- J; F+ M5 L
expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34
( B' G! Y8 S& M6 D, E5 w# ]' Jfamily members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are
1 P6 |+ ~4 L: F7 ~- SNotch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer
  v% h. s1 d8 w/ `. kstem cells.
0 F: t9 x' C/ f) p6 y. z, JMethodology/Principal Findings: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines, N; i( b7 |  F) Q, Q$ N% u2 a$ N
MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the: k3 ^, d6 s/ z/ f7 l# s. h4 h
pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2; m; @  e/ Y- d6 Q2 _5 l$ u- a
and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and
/ z9 N- H2 |0 [7 yG2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+" j7 R  z3 o! Z5 m# l% V6 m
MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high
6 p  k# \8 `  glevels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumorinitiating+ C* a* H7 q! `0 f$ ?; ^$ j7 K, _" G9 ^
cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo.
, r0 N% }5 G7 \' r+ \Conclusions/Significance: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function: P8 C* `) H& c" s
of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in- \" i( S  C- q, V
pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch,
) V9 M9 M# \8 B: g8 B9 k) Simplying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination.
7 l" d4 T7 v' kRestoration of miR-34 may hold significant promise as a novel molec

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