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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia

Zeitschrift:
Molecular Cancer > Ausgabe 1/2012
Autoren:
Xiaolu Zhang, Jiping Zeng, Minran Zhou, Bingnan Li, Yuanyuan Zhang, Tao Huang, Lixiang Wang, Jihui Jia, Chunyan Chen
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-56) contains supplementary material, which is available to authorized users.
Xiaolu Zhang, Jiping Zeng contributed equally to this work.

Competing interests

The authors declare no competing financial interests.

Authors’ contributions

JZ, CC and XZ designed the study; XZ, JZ, BL, MZ, YZ and TH performed the research; XZ ,JZ, LW, JJ, and CC analyzed and interpreted data; and XZ, JZ and CC wrote the paper. All authors read and approved the final manuscript.

Abstract

Background

Recent evidence has accumulated that MicroRNA (miRNA) dysregulation occurs in the majority of human malignancies including acute myeloid leukemia (AML) and may contribute to onco-/leukemo-genesis.

Methods

The expression levels of miR-370 and FoxM1 were assessed in 48 newly diagnosed AML patients, 40 AML patients in 1st complete remission (CR) and 21 healthy controls. Quantitative real-time PCR, western blots, colony formation assay, and β-Galactosidase ( SA- β-Gal) staining were used to characterize the changes induced by overexpression or inhibition of miR-370 or FoxM1.

Results

We found that the down-regulation of miR-370 expression was a frequent event in both leukemia cell lines and primary leukemic cells from patients with de novo AML. Lower levels of miR-370 expression were found in 37 of 48 leukemic samples from AML patients compared to those in bone marrow cells derived from healthy adult individuals. Ectopic expression of miR-370 in HL60 and K562 cells led to cell growth arrest and senescence. In contrast, depletion of miR-370 expression using RNA interference enhanced the proliferation of those leukemic cells. Mechanistically, miR-370 targets the transcription factor FoxM1, a well established oncogenic factor promoting cell cycle progression. Moreover, when HL60 and K562 cells were treated with 5-aza-2-deoxycytidine, a DNA methylation inhibitor, miR-370 expression was up-regulated, which indicates epigenetic silencing of miR-370 in leukemic cells.

Conclusions

Taken together, miR-370 may function as a tumor suppressor by targeting FoxM1, and the epigenetic silence of miR-370 thus leads to derepression of FoxM1 expression and consequently contributes to AML development and progression.
Zusatzmaterial
Additional file 1: Proliferation curve of HL60 cell line (A) and K562 cell line (B) after transfection with miR-370-expressing plasmid or the control pSilencer vector. 1 × 105/ml cells were plated in 6-well plates just before the transfection. The number of viable cells was counted at 24 h and 48 h points using trypan blue. Data represents mean ± s.e. from three separate experiments. **p < 0.01 Student’s t-test. (JPEG 50 KB)
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Additional file 2: c-Myc, hTERT, p27 kip1 and skp2 expression by qRT-PCR in 8 de novo AML patients, 8 AML patients of 1st CR and 5 healthy controls. The transcript levels of c-Myc, hTERT and skp2 in AML patients were found respectively 9.64, 3.76 and 3.14-fold higher than those in controls, while following acquisition of CR in the induction chemotherapy, all of them reduced almost to the same levels of controls. On the contrary, the expression level of p27 kip1 in AML patients is only 40% of that in controls, while restored after CR. *p < 0.05 One-Way ANOVA(JPEG 38 KB)
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Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 5
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Literatur
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