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MiR-9 upregulation leads to inhibition of erythropoiesis by repressing FoxO3.

ABSTRACT: MicroRNAs (miRNAs) are emerging as critical regulators of normal and malignant hematopoiesis. In previous studies of acute myeloid leukemia miR-9 overexpression was commonly observed. Here, we show that ectopic expression of miR-9 in vitro and in vivo significantly blocks differentiation of erythroid progenitor cells with an increase in reactive oxygen species (ROS) production. Consistent with this observation, ROS scavenging enzymes, including superoxide dismutase (Sod2), Catalase (Cat), and glutathine peroxidase (Gpx1), are down-regulated by miR-9. In addition, miR-9 suppresses expression of the erythroid transcriptional regulator FoxO3, and its down-stream targets Btg1 and Cited 2 in erythroid progenitor cells, while expression of a constitutively active form of FoxO3 (FoxO3-3A) reverses miR-9-induced suppression of erythroid differentiation, and inhibits miR-9-induced ROS production. Thus, our findings indicate that aberrant expression of miR-9 blocks erythropoiesis by deregulating FoxO3-mediated pathways, which may contribute to the ineffective erythropoiesis observed in patients with hematological malignancies.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5916915 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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miR-9 upregulation leads to inhibition of erythropoiesis by repressing FoxO3.

Zhang Yunyuan Y Li Liping L Yu Chunjie C Senyuk Vitalyi V Li Fuxing F Quigley John G JG Zhu Tongyu T Qian Zhijian Z

Scientific reports 20180425 1

MicroRNAs (miRNAs) are emerging as critical regulators of normal and malignant hematopoiesis. In previous studies of acute myeloid leukemia miR-9 overexpression was commonly observed. Here, we show that ectopic expression of miR-9 in vitro and in vivo significantly blocks differentiation of erythroid progenitor cells with an increase in reactive oxygen species (ROS) production. Consistent with this observation, ROS scavenging enzymes, including superoxide dismutase (Sod2), Catalase (Cat), and gl ...[more]

PMID: 29695725

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Project description:Organic cation transporters (human, OCT; mouse, Oct) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. The OCT1 gene SLC22A1 (human; mouse, Scl22a1) is transactivated by hepatocyte nuclear factor 4α (human, HNF4α; mouse, Hnf4α). HNF4α is a master regulator of hepatocyte differentiation and is frequently associated with hepatocellular carcinoma (HCC). In addition, the downregulation of HNF4α is associated with enhanced fibrogenesis. Our recent study revealed that hepatocarcinogenesis and fibrosis were enhanced with the loss of Oct3 (gene, Slc22a3). Notably, differences in Hnf4α expression, and in cholestasis and fibrosis were also detected in Oct3-knockout (FVB.Slc22a3tm10pb, Oct3-/-) mice. To the best of our knowledge, no data exists on an interaction between Oct3 and Hnf4α. We hypothesised that loss of Oct3 may have an impact on Hnf4α expression. In the present study, gene expression analyses were performed in liver tissue from untreated Oct3-/- and wild type (FVB, WT) mice. C57BL/6, Oct3-/- and WT mice were treated with pro-fibrotic carbon tetrachloride (CCl4) or thioacetamide (TAA) for 6 weeks to chemically induce liver fibrosis. Cholestasis-associated fibrosis was mechanically generated in Oct3-/- and WT mice by bile duct ligation (BDL). Finally, stably OCT1- and OCT3-transfected tumour cell lines and primary murine hepatocytes were treated with the non-selective OCT inhibitor quinine and Hnf4α expression was quantified by qPCR and immunofluorescence. The results revealed that Hnf4α is one of the top upstream regulators in Oct3-/- mice. Hnf4α mRNA expression levels were downregulated in Oct3-/- mice compared with in WT mice during cholestatic liver damage as well as fibrogenesis. The downregulation of Hnf4α mRNA expression in fibrotic liver tissue was reversible within 4 weeks. In stably OCT1- and OCT3-transfected HepG2 and HuH7 cells, and primary murine hepatocytes, functional inhibition of OCT led to the upregulation of Hnf4α mRNA expression. Hnf4α was revealed to be located in the cytosol of WT hepatocytes, whereas Oct3-/- hepatocytes exhibited nuclear Hnf4α expression. In conclusion, Hnf4α was downregulated in response to cholestasis and fibrosis, and functional inhibition of Oct may lead to the upregulation of Hnf4α.

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MiR-9 upregulation leads to inhibition of erythropoiesis by repressing FoxO3.

Publications

miR-9 upregulation leads to inhibition of erythropoiesis by repressing FoxO3.

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