The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia.
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.
Department of Hematology, Qilu Hospital, Shandong University, No,107, Wenhua Xi Road, Jinan, 250012, Shandong, P, R, China.
Xiaolu
X
Zhang
Jiping
J
Zeng
Minran
M
Zhou
Bingnan
B
Li
Yuanyuan
Y
Zhang
Tao
T
Huang
Lixiang
L
Wang
Jihui
J
Jia
Chunyan
C
Chen
D000293:Adolescent; D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D055815:Young Adult
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C526503:MIRN370 microRNA, human; D035683:MicroRNAs; D001374:Azacitidine