Down-regulation of miR-29c is a prognostic biomarker in acute myeloid leukemia and can reduce the sensitivity of leukemic cells to decitabine

Abstract

Background MicroRNA-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. Methods Real-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. Results MiR-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 (IC 50 ) of DAC in K562, while miR-29c silencing increased the IC 50 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 IC 50 of DAC in K562/DAC cells. Conclusions Our 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. Electronic supplementary material The online version of this article (10.1186/s12935-019-0894-y) contains supplementary material, which is available to authorized users.

Potential Role of miRNAs in the Acquisition of Chemoresistance in Neuroblastoma

“…Down-regulated in MYCN-amplified NB [22,29] and in chemoresistant NB [13] Down-regulated in cervical [30], breast [31,32] gastric [32,33], and lung [34] cancer, osteosarcoma [35], and mesothelioma [36] miR-19b 7.75 Up-regulated in chemoresistant NB [37] Down-regulated in breast [38] and colon [39] cancer and leukemia [40] miR-26b 47.87 Not evaluated Down-regulated in chemoresistant colorectal [41], gastric [42], laryngeal [43], and hepatocellular carcinoma [44,45] cancer and in glioma [46] [48], breast [49], and gastric cancer [50] miR-29c 9.27 Not evaluated Down-regulated in ovarian [51], endometrial [52], gastric [53], and small cell lung [54] cancer, glioma [55,56], and leukemia [57,58] miR-34c 7.49 Not evaluated Down-regulated in colon [59], gastric [60,61], and ovarian [62,63] cancer, and osteosarcoma [64] miR-126a 9.66 Not evaluated Down-regulated in colorectal [65] and breast cancer [66] and in renal cell carcinoma [67] miR-218 12.30…”

Identification of Acute Myeloid Leukemia Bone Marrow Circulating MicroRNAs

“…In a previous study, we demonstrated that this miRNA negatively regulates IFN-γ expression in T lymphocytes [ 83 ], and recently, we showed its direct impact on AML T lymphocyte fragility and dysfunction (in preparation). Furthermore, other downregulated miRNAs in CR1, such as miR-15b [ 84 ], miR-27a [ 85 ], miR-29c [ 86 ], miR-106a [ 87 ] and miR-181a [ 88 ], have been described as being implicated in AML pathogenesis or drug resistance.…”

Epi‐miRNAs: Modern mediators of methylation status in human cancers

“…Focusing on acute myeloid leukemia (AML), decreased circulating levels of verified DNMTs regulators, miR‐217 and miR‐29a/b/c, as well as of TET demethylases‐targeting miR‐22 could efficiently discriminate AML patients from healthy controls (Gong et al, 2014; Qu et al, 2020; Yan et al, 2018). Additionally, loss of miR‐29a/b/c in bone marrow mononuclear cells and serum miR‐22 have been correlated with unfavorable clinical disease features and significantly shorter survival (Qu et al, 2020; L. J. Tang, Sun, et al, 2019; Xiong et al, 2011; Zhu et al, 2013). Finally, despite the role of miR‐15a in attenuating multiple myeloma cell proliferation and drug resistance, reduced exosomal miR‐15a levels have been strongly associated with increased mortality rates, highlighting the dual role of miR‐15a in multiple myeloma molecular background and clinical management (F. Li, Xu, et al, 2015; Manier et al, 2017).…”

“…Focusing on acute myeloid leukemia (AML), decreased circulating levels of verified DNMTs regulators, miR-217 and miR-29a/b/c, as well as of TET demethylases-targeting miR-22 could efficiently discriminate AML patients from healthy controls (Gong et al, 2014;Qu et al, 2020;Yan et al, 2018). Additionally, loss of miR-29a/b/c in bone marrow mononuclear cells and serum miR-22 have been correlated with unfavorable clinical disease features and significantly shorter survival (Qu et al, 2020;L. J. Tang, Sun, et al, 2019;Xiong et al, 2011;Zhu et al, 2013).…”