title: Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia.
abstract: miRNA (miR) 34a has been shown to modulate critical gene transcripts involved in tumorigenesis, but its role in tumor-mediated immunosuppression is largely unknown. PD-L1 plays an important role in immune responses, however, presently its transcriptional regulatory mechanisms are not well understood. In the present study, we analyzed the expression of PD-L1 and miR-34a in 44 acute myeloid leukemia (AML) samples, and observed an inverse correlation between PD-L1 and miR-34a expression. Overexpression of miR-34a in HL-60 and Kasumi-1 cells blocked PD-L1 expression, and reduced PD-L1 surface expression. Using luciferase reporter assay and mutagenesis, we identified miR-34a as a putative binder of the PD-L1-3'UTR. Surface expression of PD-L1 induced by chemotherapeutic agents could also be reversed by miR-34a; furthermore, PD-L1 specific T cell apoptosis was reduced as well following miR-34a transfection. We also found that there is a positive feedback between PD-L1 expression and AKT activation. Our data suggest that miR-34a can regulate PD-L1 expression by targeting PD-L1 mRNA, and our present findings shed new light on the complex regulation of PD-L1 in human tumors, and on miR-34a in cancer immuno-based therapy.
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Jinge
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Dong
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Yongri
authors.initials: Y
authors.lastname: Ouyang
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Weng
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.affiliation: Department of Medical Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, PR China. Electronic address: zhzcenter@aliyun.com.
authors.forename: Huizhong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016415:Sequence Alignment; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D010087:Oxides; D034741:RNA, Small Interfering; D007371:Interferon-gamma; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000077237:Arsenic Trioxide
keywords: AML immunoresistance; PD-L1 miR-34a