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 JAK2, MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR-382-5p in PMF CD34+ 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 CD34+ cells overexpressing miR-382-5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR-382-5p. Subsequently, we confirmed miR-382-5p/SOD2 interaction by luciferase assay and we showed that miR-382-5p overexpression in CD34+ cells causes the decrease in SOD2 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 CD34+ cells restores SOD2 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 SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF-β1 signaling in PMF CD34+ cells by galunisertib significantly reduced miR-382-5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF-β1/miR-382-5p/SOD2 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.

Role of TGF-β1/miR-382-5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis / 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. - In: MOLECULAR ONCOLOGY. - ISSN 1574-7891. - 12:12(2018), pp. 2102-2123. [10.1002/1878-0261.12387]

Role of TGF-β1/miR-382-5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis

Rossi, Chiara
Investigation
;
Zini, Roberta
Supervision
;
Rontauroli, Sebastiano
Investigation
;
Ruberti, Samantha
Investigation
;
Prudente, Zelia
Investigation
;
Barbieri, Greta
Investigation
;
Bianchi, Elisa
Investigation
;
Salati, Simona
Investigation
;
Genovese, Elena
Investigation
;
Tagliafico, Enrico
Formal Analysis
;
Manfredini, Rossella
Supervision
2018

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 JAK2, MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR-382-5p in PMF CD34+ 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 CD34+ cells overexpressing miR-382-5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR-382-5p. Subsequently, we confirmed miR-382-5p/SOD2 interaction by luciferase assay and we showed that miR-382-5p overexpression in CD34+ cells causes the decrease in SOD2 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 CD34+ cells restores SOD2 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 SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF-β1 signaling in PMF CD34+ cells by galunisertib significantly reduced miR-382-5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF-β1/miR-382-5p/SOD2 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.
16-nov-2018
12
12
2102
2123
Role of TGF-β1/miR-382-5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis / 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. - In: MOLECULAR ONCOLOGY. - ISSN 1574-7891. - 12:12(2018), pp. 2102-2123. [10.1002/1878-0261.12387]
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
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