title: Revealing genome-wide mRNA and microRNA expression patterns in leukemic cells highlighted "hsa-miR-2278" as a tumor suppressor for regain of chemotherapeutic imatinib response due to targeting STAT5A.
abstract: BCR-ABL oncoprotein stimulates cell proliferation and inhibits apoptosis in chronic myeloid leukemia (CML). For cure, imatinib is a widely used tyrosine kinase inhibitor, but developing chemotherapeutic resistance has to be overcome. In this study, we aimed to determine differing genome-wide microRNA (miRNA) and messenger RNA (mRNA) expression profiles in imatinib resistant (K562/IMA-3 μM) and parental cells by targeting STAT5A via small interfering RNA (siRNA) applications. After determining possible therapeutic miRNAs, we aimed to check their effects upon cell viability and proliferation, apoptosis, and find a possible miRNA::mRNA interaction to discover the molecular basis of imatinib resistance. We detected that miR-2278 and miR-1245b-3p were most significantly regulated miRNAs according to miRNome array. Upregulating miR-2278 expression resulted in the inhibition of resistant leukemic cell proliferation and induced apoptosis, whereas miR-1245b-3p did not exhibit therapeutic results. Functional analyses indicated that AKT2, STAM2, and STAT5A mRNAs were functional targets for miR-2278 as mimic transfection decreased their expressions both at transcriptional and translational level, thus highlighting miR-2278 as a tumor suppressor. This study provides new insights in discovering the mechanism of imatinib resistance due to upregulating the tumor-suppressor hsa-miR-2278 which stands for a functional therapeutic approach, inhibited leukemic cell proliferation, induced apoptosis, and regain of chemotherapeutic drug response in CML therapy.
authors.affiliation: Medical Biology Department, Ege University Medical School, İzmir, Turkey. burcin.tezcanli@ege.edu.tr.
authors.forename: Burçin Tezcanlı
authors.initials: BT
authors.lastname: Kaymaz
authors.affiliation: Medical Biology Department, Ege University Medical School, İzmir, Turkey.
authors.forename: Nur Selvi
authors.initials: NS
authors.lastname: Günel
authors.affiliation: Oncology Department, 9 Eylül University Medical School, İzmir, Turkey.
authors.forename: Metin
authors.initials: M
authors.lastname: Ceyhan
authors.affiliation: Medical Biology Department, Ege University Medical School, İzmir, Turkey.
authors.forename: Vildan Bozok
authors.initials: VB
authors.lastname: Çetintaş
authors.affiliation: Medical Biology Department, Ege University Medical School, İzmir, Turkey.
authors.forename: Buket
authors.initials: B
authors.lastname: Özel
authors.affiliation: Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey.
authors.forename: Melis Kartal
authors.initials: MK
authors.lastname: Yandım
authors.affiliation: Medical Biology Department, Ege University Medical School, İzmir, Turkey.
authors.forename: Sezgi
authors.initials: S
authors.lastname: Kıpçak
authors.affiliation: Medical Biology Department, Ege University Medical School, İzmir, Turkey.
authors.forename: Çağdaş
authors.initials: Ç
authors.lastname: Aktan
authors.affiliation: Department of Molecular Biology and Genetics, İzmir Institute of Technology, İzmir, Turkey.
authors.forename: Aysun Adan
authors.initials: AA
authors.lastname: Gökbulut
authors.affiliation: Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, Turkey.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Baran
authors.affiliation: Medical Biology Department, Ege University Medical School, İzmir, Turkey.
authors.forename: Buket Kosova
authors.initials: BK
authors.lastname: Can
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015894:Genome, Human; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; D000068877:Imatinib Mesylate
keywords: Apoptosis; Imatinib resistance; STAT5A; Transcriptome and miRNome array; siRNA