Abstract
BackgroundMicroRNA-29c (miR-29c) is abnormally expressed in several cancers and serves as an important predictor of tumor prognosis. Herein, we investigate the effects of abnormal miR-29c expression and analyze its clinical significance in acute myeloid leukemia (AML) patients. In addition, decitabine (DAC) has made great progress in the treatment of AML in recent years, but DAC resistance is still common phenomenon and the mechanism of resistance is still unclear. We further analyze the influences of miR-29c to leukemic cells treated with DAC.MethodsReal-time quantitative PCR (RQ-PCR) was carried out to detect miR-29c transcript level in 102 de novo AML patients and 25 normal controls. miR-29c/shRNA-29c were respectively transfected into K562 cells and HEL cells. Cell viability after transfection was detected by cell counting Kit-8 assays. Flow cytometry was used to detect apoptosis.ResultsMiR-29c was significantly down-regulated in AML (P < 0.001). Low miR-29c expression was frequently observed in patients with poor karyotype and high risk (P = 0.006 and 0.013, respectively). Patients with low miR-29c expression had a markedly shorter overall survival (OS) than those with high miR-29c expression (P < 0.001). Multivariate analysis confirmed the independent prognostic value of low miR-29c expression in both the whole cohort as well as the cytogenetically normal AML (CN-AML) subset. Over-expression of miR-29c in K562 treated with DAC inhibited growth, while silencing of miR-29c in HEL promoted growth and inhibited apoptosis. MiR-29c overexpression decreased the half maximal inhibitory concentration (IC50) of DAC in K562, while miR-29c silencing increased the IC50 of DAC in HEL. The demethylation of the miR-29c promoter was associated with its up-regulated expression. Although miR-29c demethylation was also observed in DAC-resistant K562 (K562/DAC), miR-29c expression was down-regulated. MiR-29c transfection also promoted apoptosis and decreased the IC50 of DAC in K562/DAC cells.ConclusionsOur results suggest that miR-29c down-regulation may act as an independent prognostic biomarker in AML patients, and miR-29c over-expression can increase the sensitivity of both non-resistant and resistant of leukemic cells to DAC.
Highlights
MicroRNA-29c is abnormally expressed in several cancers and serves as an important predic‐ tor of tumor prognosis
The level of miR‐29c expression in normal controls and acute myeloid leukemia (AML) patients From real-time quantitative PCR (RQ-PCR) analysis, the median level of miR-29c expression was different in the normal control and AML groups (0.5703 and 0.2137, respectively)
The area under the curve (AUC) value of miR-29c was 0.753 in all AML patients and 0.763 in cytogenetically normal AML (CN-AML) patients (Fig. 1b, c), which suggested that miR-29c expression might serve as a potential biomarker in distinguishing AML patients from controls
Summary
MicroRNA-29c (miR-29c) is abnormally expressed in several cancers and serves as an important predic‐ tor of tumor prognosis. Acute myeloid leukemia (AML) is a malignant tumor of myeloid progenitor cells. It has been well established that occurrence of leukemia is the result of different genetic changes, which leads to malignant transformation [3] Epigenetic modifications such as DNA methylation and microRNA (miRNAs) expression play a key role in the pathogenesis and progression of leukemia [4,5,6,7,8,9]. A small fraction of the biological functions of miRNAs are currently elucidated These miRNAs regulate cell growth, tissue differentiation, and are involved in development and disease during life [11, 12]. This study further elucidates the roles of miR-29c in vitro with special attention to AML
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