5-aza-2′-deoxycytidine promotes migration of acute monocytic leukemia cells via activation of CCL2-CCR2-ERK signaling pathway

Xiao, Xianmin; Xu, Qiong; Sun, Yan; Lu, Ziwei; Li, Rui; Wang, Xinxin; Jiang, Xin; Zhang, Guirong; Xiao, Yong

doi:10.3892/mmr.2017.6737

Cited by 8 publications

(6 citation statements)

References 24 publications

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“…As a genome-wide demethylation drug, 5-aza-dC can affect diverse signalling pathways. Indeed, it has been reported that 5-aza-dC indirectly activates ERK through CCL2 and CCR-2 in human monocytic leukaemia cells [ 41 ].…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of miR-29a/miR-30c/DNMT3A axis controls SOD2 and mitochondrial oxidative stress in human mesenchymal stem cells

Jung¹,

Park²,

Kang³

et al. 2020

Redox Biology

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The use of human mesenchymal stem cells (hMSCs) in clinical applications requires large-scale cell expansion prior to administration. However, the prolonged culture of hMSCs results in cellular senescence, impairing their proliferation and therapeutic potentials. To understand the role of microRNAs (miRNAs) in regulating cellular senescence in hMSCs, we globally depleted miRNAs by silencing the DiGeorge syndrome critical region 8 ( DGCR8 ) gene, an essential component of miRNA biogenesis. DGCR8 knockdown hMSCs exhibited severe proliferation defects and senescence-associated alterations, including increased levels of reactive oxygen species (ROS). Transcriptomic analysis revealed that the antioxidant gene superoxide dismutase 2 ( SOD2 ) was significantly downregulated in DGCR8 knockdown hMSCs. Moreover, we found that DGCR8 silencing in hMSCs resulted in hypermethylation in CpG islands upstream of SOD2 . 5-aza-2′-deoxycytidine treatment restored SOD2 expression and ROS levels. We also found that these effects were dependent on the epigenetic regulator DNA methyltransferase 3 alpha (DNMT3A). Using computational and experimental approaches, we demonstrated that DNMT3A expression was regulated by miR-29a-3p and miR-30c-5p. Overexpression of miR-29a-3p and/or miR-30c-5p reduced ROS levels in DGCR8 knockdown hMSCs and rescued proliferation defects, mitochondrial dysfunction, and premature senescence. Our findings provide novel insights into hMSCs senescence regulation by the miR-29a-3p/miR-30c-5p/DNMT3A/SOD2 axis.

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Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of miR-29a/miR-30c/DNMT3A axis controls SOD2 and mitochondrial oxidative stress in human mesenchymal stem cells

Jung¹,

Park²,

Kang³

et al. 2020

Redox Biology

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“…The compound 5-Aza-2-deoxycytidine is a demethylating agent that causes genome-wide hypomethylation and inhibits cancer cell growth [9]. It plays a dominant role in the treatment of myelodysplastic syndrome and acute myeloid leukemia (AML) [10]. In most GC cells, HHIP promoter methylation and cancer cell proliferation were both suppressed by 5-Aza-dc [11].…”

Section: Introductionmentioning

confidence: 99%

Hypermethylated long noncoding RNA MEG3 promotes the progression of gastric cancer

Ding

Tian

et al. 2019

Aging

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This study aims to explore the expression and degree of methylation of lncRNA MEG3 in gastric cancer tissues and to analyze its effect on the migration and proliferation of gastric cancer patients and the mechanism by which this occurs. The targeting relationship between MEG3, miR-181a-5p and ATP4B was detected through molecular biology experiments. Wound healing, transwell, colony formation and flow cytometry assays were used to analyze the effects of lncRNA MEG3 and methylation on tumor cell migration, invasion, proliferation and apoptosis. In addition, a tumor xenotransplantation model was established to study the influence of MEG3 on tumor growth in vivo. Bioinformatics analysis showed that lncRNA MEG3 and ATP4B were downregulated in gastric cancer tissues compared with normal tissues. Bioinformatics predicted that ATP4B might be regulated by targeting miR-181a-5p. The overexpression of MEG3 and the application of 5-Aza treatment inhibited the migration, invasion and proliferation of MGC-803 cells and promoted apoptosis. In gastric cancer tissues, MEG3 is hypermethylated to decrease expression. Once the expression of MEG3 is restored or methylation is inhibited, tumor growth can be inhibited both in vivo and in vitro. This finding could be utilized as a clinical reference for gastric cancer treatment in the future.

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“…STAT3 activation by IL‐6 is the mechanistic basis of the chronic inflammation frequently seen during tumour development (Munoz et al , ; Johnson et al , ). IL‐6 binding to its receptor initiates both the JAK/STAT and MAPK pathways (Heinrich et al , ), while MCP‐1 increases the level of p‐STAT3 and p‐ERK in AML (Xiao et al , ; Ma et al , ). Redell et al () demonstrated that targetting the G‐CSF‐induced STAT3 activation triggered apoptosis in the AML cells.…”

Section: Discussionmentioning

confidence: 99%

Upregulation ofAKR1C1in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells

et al. 2020

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The leukaemic bone marrow microenvironment, comprising abnormal mesenchymal stromal cells (MSCs), is responsible for the poor prognosis of acute myeloid leukaemia (AML). Therefore, it is essential to determine the mechanisms underlying the supportive role of MSCs in the survival of leukaemia cells. Through in silico analyses, we identified a total of 271 aberrantly expressed genes in the MSCs derived from acute myeloid leukemia (AML) patients that were associated with adipogenic differentiation, of which aldo-keto reductase 1C1 (AKR1C1) was significantly upregulated in the AML-MSCs. Knockdown of AKR1C1 in the MSCs suppressed adipogenesis and promoted osteogenesis, and inhibited the growth of co-cultured AML cell lines compared to the situation in wild-type AML-derived MSCs. Introduction of recombinant human AKR1C1 in the MSCs partially alleviated the effects of AKR1C1 knockdown. In addition, the absence of AKR1C1 reduced secretion of cytokines such as MCP-1, IL-6 and G-CSF from the MSCs, along with inactivation of STAT3 and ERK1/2 in the cocultured AML cells. AKR1C1 is an essential factor driving the adipogenic differentiation of leukaemic MSCs and mediates its pro-survival effects on AML cells by promoting cytokine secretion and activating the downstream pathways in the AML cells.

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5-aza-2′-deoxycytidine promotes migration of acute monocytic leukemia cells via activation of CCL2-CCR2-ERK signaling pathway

Cited by 8 publications

References 24 publications

Epigenetic regulation of miR-29a/miR-30c/DNMT3A axis controls SOD2 and mitochondrial oxidative stress in human mesenchymal stem cells

Epigenetic regulation of miR-29a/miR-30c/DNMT3A axis controls SOD2 and mitochondrial oxidative stress in human mesenchymal stem cells

Hypermethylated long noncoding RNA MEG3 promotes the progression of gastric cancer

Upregulation ofAKR1C1in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells

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