标题: MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells [打印本页] 作者: 饶冠华 时间: 2010-1-7 15:24 标题: MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells
PLoS One. 2009 Aug 28;4(8):e6816." Q) D& z9 v" G6 M
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MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.8 |) z7 N3 y$ q
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. % h% i# z$ u S2 F' |6 K9 l! p4 F j% `/ m( `& l
Department of Radiation Oncolog, University of Michigan, Ann Arbor, Michigan, United States of America.4 D" |2 H2 }" J$ E5 S k( b
' `) K1 X0 e# K1 i! r! zBACKGROUND: 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. " }/ T3 L$ q+ p" \, e$ ~4 C 4 M B7 W7 l, V: ^+ t$ {6 LPMID: 19714243 [PubMed - in process]作者: mqz_11 时间: 2010-1-8 17:31