PMID- 27517565 OWN - NLM STAT- MEDLINE DCOM- 20170228 LR - 20181113 IS - 1423-0380 (Electronic) IS - 1010-4283 (Linking) VI - 37 IP - 10 DP - 2016 Oct TI - miR-101 sensitizes K562 cell line to imatinib through Jak2 downregulation and inhibition of NF-kappaB target genes. PG - 14117-14128 AB - 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. FAU - Farhadi, Elham AU - Farhadi E AD - Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran. FAU - Zaker, Farhad AU - Zaker F AD - Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran. farhadz20@yahoo.co.uk. AD - Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran. farhadz20@yahoo.co.uk. FAU - Safa, Majid AU - Safa M AD - Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran. AD - Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran. FAU - Rezvani, Mohammad Reza AU - Rezvani MR AD - Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, 1449614535, Iran. AD - Immune and Gene Therapy Laboratory, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. LA - eng PT - Journal Article DEP - 20160812 PL - Netherlands TA - Tumour Biol JT - Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine JID - 8409922 RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (MIRN101 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (NF-kappa B) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 8A1O1M485B (Imatinib Mesylate) RN - EC 2.7.10.2 (JAK2 protein, human) RN - EC 2.7.10.2 (Janus Kinase 2) SB - IM MH - Antineoplastic Agents/pharmacology MH - Apoptosis/drug effects MH - Biomarkers, Tumor/genetics MH - Cell Cycle/drug effects MH - Cell Proliferation/drug effects MH - Drug Resistance, Neoplasm/*genetics MH - Flow Cytometry MH - Gene Expression Regulation, Neoplastic/*drug effects MH - Humans MH - Imatinib Mesylate/*pharmacology MH - Janus Kinase 2/*antagonists & inhibitors/genetics/metabolism MH - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*genetics/pathology MH - MicroRNAs/*genetics MH - NF-kappa B/*antagonists & inhibitors/genetics/metabolism MH - RNA, Messenger/genetics MH - RNA, Small Interfering/genetics MH - Real-Time Polymerase Chain Reaction MH - Reverse Transcriptase Polymerase Chain Reaction MH - Tumor Cells, Cultured OTO - NOTNLM OT - Apoptosis OT - CML OT - Imatinib OT - Jak2 OT - miR-101 EDAT- 2016/08/16 06:00 MHDA- 2017/03/01 06:00 CRDT- 2016/08/13 06:00 PHST- 2016/03/14 00:00 [received] PHST- 2016/07/13 00:00 [accepted] PHST- 2016/08/16 06:00 [pubmed] PHST- 2017/03/01 06:00 [medline] PHST- 2016/08/13 06:00 [entrez] AID - 10.1007/s13277-016-5205-9 [pii] AID - 10.1007/s13277-016-5205-9 [doi] PST - ppublish SO - Tumour Biol. 2016 Oct;37(10):14117-14128. doi: 10.1007/s13277-016-5205-9. Epub 2016 Aug 12.