title: miR-101 sensitizes K562 cell line to imatinib through Jak2 downregulation and inhibition of NF-κB target genes.
abstract: Imatinib mesylate (IM) is a frontline treatment in the early chronic phase of chronic myeloid leukemia (CML). However, intrinsic and acquired resistance against this drug has been defined and this issue has become a problem and a challenge in CML treatment. According to new findings, the inhibition of Janus kinase 2 (Jak2) in Bcr-Abl+ cells can promote apoptosis in IM-resistant cells. microRNAs (miRNAs) regulate the gene expression by targeting the messenger RNA (mRNA) for degradation. Recently, a growing body of evidence has implicated that dysregulation of miRNAs is associated with cancer initiation and development. In this report, we proposed that miRNA-101 targets Jak2 mRNA and regulates its expression and induces K562 leukemia cell apoptosis. Here, we transduced the K562 cell line with a miR-101-overexpressing vector and evaluated the Jak2 mRNA level. Our results showed that miR-101 overexpression in Bcr-Abl+ cells reduced the Jak2 mRNA level. Moreover, imatinib treatment and miR-101 upregulation led to miR-23a overexpression, which has putative binding site(s) on 3'-untranslated regions (3'-UTRs) of STAT5, CCND1, and Bcl-2 genes. Our results also indicated that miR-101 overexpression inhibited cell proliferation indicated by the MTT assay and promoted apoptosis detected via flow cytometry. Importantly, mRNA expression of NF-kappa B-regulated anti-apoptotic (Bcl-2, Bcl-xl, MCL-1, XIAP, and survivin) and proliferative (c-Myc and CCND1) genes was decreased. These findings suggest that miR-101 acts as a tumor suppressor by downregulating Jak2 expression and sensitizing K562 cells to imatinib. Therefore, restoration of miR-101 may be a therapeutic approach for CML treatment.
authors: Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran.
authors: Elham
authors: E
authors: Farhadi
authors: Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran. farhadz20@yahoo.co.uk.|Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran. farhadz20@yahoo.co.uk.
authors: Farhad
authors: F
authors: Zaker
authors: Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran.|Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors: Majid
authors: M
authors: Safa
authors: Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran.|Immune and Gene Therapy Laboratory, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Mohammad Reza
authors: MR
authors: Rezvani
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Apoptosis; CML; Imatinib; Jak2; miR-101