> Details
Rossi, Chiara;
Zini, Roberta;
Rontauroli, Sebastiano;
Ruberti, Samantha;
Prudente, Zelia;
Barbieri, Greta;
Bianchi, Elisa;
Salati, Simona;
Genovese, Elena;
Bartalucci, Niccolò;
Guglielmelli, Paola;
Tagliafico, Enrico;
Rosti, Vittorio;
Barosi, Giovanni;
Vannucchi, Alessandro M.;
Manfredini, Rossella
Role of TGF‐β1/miR‐382‐5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis
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- Media type: E-Article
- Title: Role of TGF‐β1/miR‐382‐5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis
- Contributor: Rossi, Chiara; Zini, Roberta; Rontauroli, Sebastiano; Ruberti, Samantha; Prudente, Zelia; Barbieri, Greta; Bianchi, Elisa; Salati, Simona; Genovese, Elena; Bartalucci, Niccolò; Guglielmelli, Paola; Tagliafico, Enrico; Rosti, Vittorio; Barosi, Giovanni; Vannucchi, Alessandro M.; Manfredini, Rossella
- imprint: Wiley, 2018
- Published in: Molecular Oncology
- Language: English
- DOI: 10.1002/1878-0261.12387
- ISSN: 1574-7891; 1878-0261
- Keywords: Cancer Research ; Genetics ; Molecular Medicine ; General Medicine ; Oncology
- Origination:
- Footnote:
- Description: <jats:sec><jats:label /><jats:p>Primary myelofibrosis (<jats:styled-content style="fixed-case">PMF</jats:styled-content>) 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 <jats:italic><jats:styled-content style="fixed-case">JAK</jats:styled-content>2</jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">MPL</jats:styled-content>,</jats:italic> and <jats:italic><jats:styled-content style="fixed-case">CALR</jats:styled-content></jats:italic> genes, the deregulation of mi<jats:styled-content style="fixed-case">RNA</jats:styled-content> expression may also contribute to the pathogenesis of <jats:styled-content style="fixed-case">PMF</jats:styled-content>. To this end, we recently reported the upregulation of miR‐382‐5p in <jats:styled-content style="fixed-case">PMF CD</jats:styled-content>34+ cells. In order to unveil the mechanistic details of the role of miR‐382‐5p in pathogenesis of <jats:styled-content style="fixed-case">PMF</jats:styled-content>, we performed gene expression profiling of <jats:styled-content style="fixed-case">CD</jats:styled-content>34+ cells overexpressing miR‐382‐5p. Among the downregulated genes, we identified superoxide dismutase 2 (<jats:italic><jats:styled-content style="fixed-case">SOD</jats:styled-content>2</jats:italic>), which is a predicted target of miR‐382‐5p. Subsequently, we confirmed miR‐382‐5p/<jats:italic><jats:styled-content style="fixed-case">SOD</jats:styled-content>2</jats:italic> interaction by luciferase assay and we showed that miR‐382‐5p overexpression in <jats:styled-content style="fixed-case">CD</jats:styled-content>34+ cells causes the decrease in <jats:styled-content style="fixed-case">SOD</jats:styled-content>2 activity leading to reactive oxygen species (<jats:styled-content style="fixed-case">ROS</jats:styled-content>) accumulation and oxidative <jats:styled-content style="fixed-case">DNA</jats:styled-content> damage. In addition, our data indicate that inhibition of miR‐382‐5p in <jats:styled-content style="fixed-case">PMF CD</jats:styled-content>34+ cells restores <jats:styled-content style="fixed-case">SOD</jats:styled-content>2 function, induces <jats:styled-content style="fixed-case">ROS</jats:styled-content> disposal, and reduces <jats:styled-content style="fixed-case">DNA</jats:styled-content> oxidation. Since the pro‐inflammatory cytokine transforming growth factor‐β1 (<jats:styled-content style="fixed-case">TGF</jats:styled-content>‐β1) is a key player in <jats:styled-content style="fixed-case">PMF</jats:styled-content> pathogenesis, we further investigated the effect of <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐β1 on <jats:styled-content style="fixed-case">ROS</jats:styled-content> and miR‐382‐5p levels. Our data showed that <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐β1 treatment enhances miR‐382‐5p expression and reduces <jats:styled-content style="fixed-case">SOD</jats:styled-content>2 activity leading to <jats:styled-content style="fixed-case">ROS</jats:styled-content> accumulation. Finally, inhibition of <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐β1 signaling in <jats:styled-content style="fixed-case">PMF CD</jats:styled-content>34+ cells by galunisertib significantly reduced miR‐382‐5p expression and <jats:styled-content style="fixed-case">ROS</jats:styled-content> accumulation and restored <jats:styled-content style="fixed-case">SOD</jats:styled-content>2 activity. As a whole, this study reports that <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐β1/miR‐382‐5p/<jats:styled-content style="fixed-case">SOD</jats:styled-content>2 axis deregulation in <jats:styled-content style="fixed-case">PMF</jats:styled-content> cells is linked to <jats:styled-content style="fixed-case">ROS</jats:styled-content> 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 <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐β1 in <jats:styled-content style="fixed-case">PMF</jats:styled-content> patients.</jats:p></jats:sec><jats:sec><jats:title>Database linking</jats:title><jats:p>GEO: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464">https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464</jats:ext-link>.</jats:p></jats:sec>
- Access State: Open Access