title: MiR-424 and miR-27a increase TRAIL sensitivity of acute myeloid leukemia by targeting PLAG1.
abstract: Although microRNAs have been elaborated to participate in various physiological and pathological processes, their functions in TRAIL resistance of acute myeloid leukemia (AML) remain obscure. In this study, we detected relatively lower expression levels of miR-424&27a in TRAIL-resistant and semi-resistant AML cell lines as well as newly diagnosed patient samples. Overexpression of miR-424&27a, by targeting the 3'UTR of PLAG1, enhanced TRAIL sensitivity in AML cells. Correspondingly, knockdown of PLAG1 sensitized AML cells to TRAIL-induced apoptosis and proliferation inhibition. We further found that PLAG1 as a transcription factor could reinforce Bcl2 promoter activity, causing its upregulation at the mRNA level. Both downregulated PLAG1 and elevated expression of miR-424&27a led to Bcl2 downregulation and augmented cleavage of Caspase8, Caspase3 and PARP in the presence of TRAIL. Restoration of Bcl2 could eliminate their effects on AML TRAIL sensitization. Overall, we propose that miR-424&27a and/or PLAG1 might serve as novel therapeutic targets in AML TRAIL therapy.
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Sun
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Han
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: A-Min
authors.initials: AM
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Hong-Chun
authors.initials: HC
authors.lastname: Wang
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Dao-Xin
authors.initials: DX
authors.lastname: Ma
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Ji
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002648:Child; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C531388:MIRN27 microRNA, human; C554214:MIRN424 microrna, human; D035683:MicroRNAs; C104382:PLAG1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: PLAG1; TRAIL resistance; acute myeloid leukemia; miR-27a; miR-424