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

Li-Juan Tang; Guo-Kang Sun; Ting-Juan Zhang; De-Hong Wu; Jing-Dong Zhou; Bei-Bei Ma; Zi-Jun Xu; Xiang-Mei Wen; Qin Chen; Dong-Ming Yao; Jun Qian; Ji-Chun Ma; Jiang Lin

doi:10.1186/s12935-019-0894-y

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

Cancer Cell Int. 2019 Jul 10:19:177. doi: 10.1186/s12935-019-0894-y. eCollection 2019.

Authors

Li-Juan Tang^#^{1

2}, Guo-Kang Sun^#^{1

2}, Ting-Juan Zhang^#^{1

2}, De-Hong Wu³, Jing-Dong Zhou^{1

2}, Bei-Bei Ma^{1

2}, Zi-Jun Xu^{1

2}, Xiang-Mei Wen^{1

2}, Qin Chen^{1

2}, Dong-Ming Yao^{1

2}, Jun Qian⁴, Ji-Chun Ma¹, Jiang Lin¹

Affiliations

¹ 1Laboratory Center, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002 People's Republic of China.
² The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu People's Republic of China.
³ Department of Hematology, The Third People's Hospital of Kunshan City, 615 Zizhu Rd, Kunshan, 215300 People's Republic of China.
⁴ 2Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002 People's Republic of China.

^# Contributed equally.

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 (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.

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.

Keywords: Acute myeloid leukemia; Decitabine; MiR-29c expression; Prognostic.