Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and may progress to acute myeloid leukemia (AML). MicroRNAs (miRNA/miRs) as oncogenes or tumor suppressors regulate a number of biological processes including cell proliferation, cell cycle and apoptosis in different types of cancer cells. Recently, it has been reported that miR-21 as an oncogene is overexpressed and directly targets SMAD-7 in MDS. However, little is known about the mechanism of miR-21 in the progression of MDS. In the present study, the role of miR-21 in the proliferation and apoptosis of SKM-1 cells, an acute myeloid leukemia cell line established in the AML/MDS leukemic phase was investigated. The present results demonstrated that downregulation of miR-21 inhibited proliferation, induced apoptosis and caused G1 phase cell cycle arrest of SKM-1 cells. In addition, the expression levels of apoptosis regulator Bcl-2 (bcl2), cyclinD1 and phosphorylated-protein kinase B (AKT) were significantly decreased in SKM-1 cells transfected with the miR-21 inhibitor, whilst the expression levels of phosphatase and tensin homolog (PTEN), bcl-associated protein X (bax) and cleaved caspase 3 were significantly elevated. Furthermore, knockdown of Akt by small interfering (si)RNA significantly increased the expression of bax, cleaved caspase 3 and reduced the expression of bcl2 and cyclinD1 in SKM-1 cells. Taken together, these data indicate that miR-21 targets the PTEN/AKT pathway in the pathogenesis of MDS and could be a potential target for MDS therapy.
Acute myeloid leukemia (AML) is the most lethal hematological malignancy, and the occurrence of chemoresistance prevents the achievement of complete remission following the standard therapy. MicroRNAs have been extensively investigated as critical regulators of hematopoiesis and leukemogenesis, and they represent a promising strategy for AML therapy. In this study, we identified miR-34b as a novel regulator in myeloid proliferation and apoptosis of leukemic cells. We found that miR-34b was developmentally upregulated in plasma and myeloid cells of healthy subjects, while it was significantly reduced in blood samples of patients with AML and AML cell lines. Moreover, the miR-34b mimicked transfection-mediated restoration of miR-34b inhibited cell viability and promoted cell apoptosis of HL-60 and OCI-AML3 cell lines. Using a miRNA predicting algorithm miRanda, we selected a potent target heat shock transcription factor 1 (HSF1) since that is a master regulator of the heat shock response and is associated with cancer aggressiveness and dissemination. In contrast to the level of miR-34b, HSF1 was highly expressed in blood samples of patients with AML and AML cell lines. The luciferase reporter assay revealed that miR-34b directly targeted the HSF1 gene. HSF1 silencing exhibited comparable inhibitory effects on AML cell proliferation and survival. The upregulated HSF1 elevated the activation of the Wnt-β-catenin pathway. In conclusion, miR-34b suppressed AML cell proliferation and survival by targeting HSF1, in turn leading to the inactivation of Wnt-β-catenin pathway, which may highlight a new therapeutic approach for AML.
The present study assessed the mechanism underlying the effect of sorafenib on the proliferation and apoptosis of the acute promyelocytic leukemia (APL) cell line NB4. NB4 cells were treated with different concentrations of sorafenib (0, 1.5, 3, 6, and 12 µM) for 24, 48 and 72 h. Cell proliferation, cell cycle, and apoptosis were analyzed using an MTT assay and flow cytometry analysis, respectively. Reverse transcription-semi-quantitative polymerase chain reaction and western blot analysis were performed to assess the expression of caspase-3, caspase-8, myeloid cell leukemia (MCL)1, cyclin D1, mitogen-activated protein kinase (MEK), phosphorylated (P)-MEK, extracellular signal-regulated kinase (ERK) and P-ERK. The results of the MTT assay demonstrated that, compared with untreated cells, the proliferation of sorafenib-treated NB4 cells was inhibited dose- and time-dependently. Furthermore, cell cycle arrest was induced in the G0/G1 phase and cell apoptosis was promoted in a dose-dependent manner in sorafenib-treated NB4 cells compared with untreated cells. In addition, the expression of the proapoptotic molecules caspase-3 and caspase-8 was significantly upregulated, and the expression of the antiapoptotic molecule MCL1 and the cell cycle-associated cyclin D1 was downregulated in sorafenib-treated NB4 cells compared with untreated cells. Furthermore, the phosphorylation of MEK and ERK was inhibited in sorafenib-treated NB4 cells compared with untreated cells. Sorafenib may inhibit proliferation and induce cell cycle arrest and apoptosis in APL cells. The underlying mechanisms of such effects may be associated with alterations to the expression of apoptosis-associated and cell cycle-associated molecules via MEK/ERK signaling pathway inhibition.
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