title: Epigenetic deregulated miR-375 contributes to the constitutive activation of JAK2/STAT signaling in myeloproliferative neoplasm.
abstract: Constitutive activation of Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling caused by JAK2V617F and other mutations is central to the pathogenesis of myeloproliferative neoplasm (MPN). Negative regulators such as suppressors of cytokine signaling (SOCS) inhibit activated JAK2/STAT signaling. However, whether silencing of negative regulators facilitates JAK2/STAT signaling is unclear. Here, we report that loss of miR-375 expression contributes to the constitutive activation of JAK2/STAT signaling. MiR-375 reduced JAK2 protein level and repressed the activity of a luciferase reporter by binding 3'-untranslated regions, which was abolished by the mutation of the predicted miR-375-binding site. Meanwhile, a significant inverse correlation between the expressions of miR-375 and JAK2 was found in multiple types of leukemic cell lines and bone marrow mononuclear cells from MPN patients, suggesting that JAK2 may be a miR-375 target gene. Furthermore, forced expression of miR-375 inhibited constitutive and inducible JAK2/STAT signaling, suppressed cell proliferation, and decreased colony formation in hematopoietic progenitors from MPN patients. Finally, histone deacetylation (HDAC) inhibitors restored miR-375 expression, which was much lower in patients with MPN compared with healthy volunteers. Collectively, our data suggest that the loss of miR-375 expression enhances the constitutive and persistent activation of JAK2/STAT signaling. Restoration of miR-375 expression might contribute to the clinical treatment for MPN patients.
authors: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, 2 FuXue Road, Wenzhou 325000, China.
authors: Li-hui
authors: LH
authors: Yin
authors: Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuanxi Road, Wenzhou 325000, China; School of Laboratory Medicine, Wenzhou Medical University, Chashan University Town, Wenzhou 325000, China.
authors: Xiao-qun
authors: XQ
authors: Zheng
authors: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, 2 FuXue Road, Wenzhou 325000, China.
authors: Hai-ying
authors: HY
authors: Li
authors: Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, 2 FuXue Road, Wenzhou 325000, China.
authors: Lai-xi
authors: LX
authors: Bi
authors: Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, 2 FuXue Road, Wenzhou 325000, China.
authors: Yi-fen
authors: YF
authors: Shi
authors: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, 2 FuXue Road, Wenzhou 325000, China.
authors: Ai-fang
authors: AF
authors: Ye
authors: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, 2 FuXue Road, Wenzhou 325000, China.
authors: Jian-bo
authors: JB
authors: Wu
authors: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, 2 FuXue Road, Wenzhou 325000, China. Electronic address: gaoshenmeng77@126.com.
authors: Shen-meng
authors: SM
authors: Gao
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D050791:STAT Transcription Factors; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Epigenetics; MPN; miRNA