In:
Molecular Oncology, Wiley, Vol. 12, No. 12 ( 2018-12), p. 2102-2123
Abstract:
Primary myelofibrosis ( PMF ) is a myeloproliferative neoplasm characterized by an excessive production of pro‐inflammatory cytokines resulting in chronic inflammation and genomic instability. Besides the driver mutations in JAK 2 , MPL , and CALR genes, the deregulation of mi RNA expression may also contribute to the pathogenesis of PMF . To this end, we recently reported the upregulation of miR‐382‐5p in PMF CD 34+ cells. In order to unveil the mechanistic details of the role of miR‐382‐5p in pathogenesis of PMF , we performed gene expression profiling of CD 34+ cells overexpressing miR‐382‐5p. Among the downregulated genes, we identified superoxide dismutase 2 ( SOD 2 ), which is a predicted target of miR‐382‐5p. Subsequently, we confirmed miR‐382‐5p/ SOD 2 interaction by luciferase assay and we showed that miR‐382‐5p overexpression in CD 34+ cells causes the decrease in SOD 2 activity leading to reactive oxygen species ( ROS ) accumulation and oxidative DNA damage. In addition, our data indicate that inhibition of miR‐382‐5p in PMF CD 34+ cells restores SOD 2 function, induces ROS disposal, and reduces DNA oxidation. Since the pro‐inflammatory cytokine transforming growth factor‐β1 ( TGF ‐β1) is a key player in PMF pathogenesis, we further investigated the effect of TGF ‐β1 on ROS and miR‐382‐5p levels. Our data showed that TGF ‐β1 treatment enhances miR‐382‐5p expression and reduces SOD 2 activity leading to ROS accumulation. Finally, inhibition of TGF ‐β1 signaling in PMF CD 34+ cells by galunisertib significantly reduced miR‐382‐5p expression and ROS accumulation and restored SOD 2 activity. As a whole, this study reports that TGF ‐β1/miR‐382‐5p/ SOD 2 axis deregulation in PMF cells is linked to ROS overproduction that may contribute to enhanced oxidative stress and inflammation. Our results suggest that galunisertib may represent an effective drug reducing abnormal oxidative stress induced by TGF ‐β1 in PMF patients. Database linking GEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464 .
Type of Medium:
Online Resource
ISSN:
1574-7891
,
1878-0261
DOI:
10.1002/mol2.2018.12.issue-12
DOI:
10.1002/1878-0261.12387
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2322586-5
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