|
  
- 积分
- 4277
- 威望
- 4277
- 包包
- 7646
|
PLoS One. 2009 Aug 28;4(8):e6816.: w5 \/ N3 o' K
3 k- F+ r" ^/ J0 PMicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.2 Y5 S$ F3 P' @
Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L, Xiang D, Desano JT, Bommer GT, Fan D, Fearon ER, Lawrence TS, Xu L.
! b: ]3 j) Z Q# H+ {- c+ \0 ]. N0 n$ t" u1 Z
Department of Radiation Oncolog, University of Michigan, Ann Arbor, Michigan, United States of America.7 _7 `1 ~% e! k3 Y
) N% `( Y [1 V6 Q
BACKGROUND: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells. METHODOLOGY/PRINCIPAL FINDINGS: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+ MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53-miR34, potentially via inhibiting pancreatic cancer stem cells.
# w% V6 H$ l$ z3 ~2 e6 D/ T9 H& X5 @6 y8 c8 ?6 l
PMID: 19714243 [PubMed - in process] |
附件: 你需要登录才可以下载或查看附件。没有帐号？注册
-
总评分: 威望 + 10
包包 + 10
查看全部评分
|
发表于 2010-1-7 15:24
发表于 2010-1-8 17:31
