Suppression of miR-708 inhibits the Wnt/β-catenin signaling pathway by activating DKK3 in adult B-all
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Yingjie Zhang1,*, Huibo Li1,*, Rongyi Cao1,*, Lili Sun1, Yan Wang1, Shengjin Fan1, Yanqiu Zhao1, Desheng Kong1, Lin Cui1, Leilei Lin1, Ke Wang1, Yinghua Li1,2 and Jin Zhou1,2
1Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
2Heilongjiang Academy of Medical Science, Harbin, China
*These authors have contributed equally to this work
Keywords: adult B-acute lymphoblastic leukemia, miR-708, 5-aza-2’-deoxycytidine, DKK3, Wnt/β-catenin
Received: July 20, 2016 Accepted: June 13, 2017 Published: July 18, 2017
Inactivation of Dickkopf-3 (DKK3) is closely associated with a poor prognosis in various solid tumor and hematologic malignancies. Promoter hypermethylation is one potential cause of DKK3 inactivation. However, whether other mechanisms lead to DKK3 inactivation and the subsequent effects of these inactivations on cell proliferation and the Wnt signaling pathway in adult B acute lymphoblastic leukemia (B-ALL) remain unclear. In the present study, we found that low DKK3 expression levels were associated with high miR-708 expression and promoter hypermethylation in adult B-ALL. miR-708 was confirmed to directly decrease DKK3 expression in Nalm-6 and BALL-1 cells. Additionally, a miR-708 inhibitor decreased cell proliferation mainly through apoptosis and cell cycle arrest at the G1 phase, and these effects were eliminated by DKK3 siRNA treatment. Moreover, the demethylating agent 5-aza-2’-deoxycytidine (5-aza) decreased the methylation state of the DKK3 promoter based on methylation-specific PCR (MSP) and bisulfite genomic sequencing PCR (BSP), although this demethylation effect was not enhanced by the miR-708 inhibitor. The miR-708 inhibitor or 5-aza significantly increased DKK3 expression and decreased p-GSK3β, cyclin D1 and nuclear and cytoplasmic β-catenin protein expression, indicating that the Wnt/β-catenin signaling pathway was inhibited. These effects became more pronounced when the miR-708 inhibitor and 5-aza were used simultaneously. These findings provide greater insights into the mechanisms that increase DKK3 expression and suggest that a miR-708 inhibitor and 5-aza might be useful as targeted therapies for adult B-ALL.
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