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Aging (Albany NY). 2019 May 30;11(10):3376-3391. doi: 10.18632/aging.101991.

MicroRNA-335/ID4 dysregulation predicts clinical outcome and facilitates leukemogenesis by activating PI3K/Akt signaling pathway in acute myeloid leukemia.

Zhou JD#1,2,3, Li XX#4, Zhang TJ#1,2,3, Xu ZJ2,3,5, Zhang ZH6, Gu Y1,2,3, Wen XM2,3,5, Zhang W1,2,3, Ji RB2,5, Deng ZQ2,3,5, Lin J2,3,5, Qian J1,2,3.

Author information

1
Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
2
Zhenjiang Clinical Research Center of Hematology, Zhenjiang, People's Republic of China.
3
The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, People's Republic of China.
4
Department of Hematology, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
5
, Laboratory Center, Affiliated People's Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
6
Department of Geriatrics, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
#
Contributed equally

Abstract

MircoRNA-335 (miR-335) has been reported as a significant cancer-associated microRNA, which was often epigenetically silenced and acted as a tumor suppressor gene in diverse human solid tumors. Conversely, recent studies show that miR-335 overexpression was identified in both adult and pediatric acute myeloid leukemia (AML), suggesting that it might play an oncogenic role of miR-335 in AML. However, the role of miR-335 during leukemogenesis remains to be elucidated. MiR-335/ID4 expression was detected by real-time quantitative PCR and/or western blot. Survival analysis was performed to explore the association between miR-335/ID4 expression and the prognosis, and further validated by public databases. Gain-of-function experiments determined by cell proliferation, apoptosis, and differentiation were conducted to investigate the biological functions of miR-335/ID4. Herein, we found that miR-335 expression, independent of its methylation, was significantly increased and negatively correlated with reduced ID4 expression in AML. Moreover, aberrant miR-335/ID4 expression independently affected chemotherapy response and leukemia-free/overall survival in patients with AML. Gain-of-function experiments in vitro showed the oncogenic role of miR-335 by affecting cell apoptosis and proliferation in AML, and could be rescued by ID4 restoration. Mechanistically, we identified and verified that miR-335/ID4 contributed to leukemogenesis through activating PI3K/Akt signaling pathway. Collectively, aberrant miR-335/ID4 expression was an independent prognostic biomarker in AML. MiR-335/ID4 dysregulation facilitated leukemogenesis through the activation of PI3K/Akt signaling pathway.

KEYWORDS:

ID4; MiR-335; PI3K/Akt pathway; acute myeloid leukemia; prognosis

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