Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia

Cell Signal. 2015 Mar;27(3):443-52. doi: 10.1016/j.cellsig.2014.12.003. Epub 2014 Dec 10.


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.

Keywords: AML immunoresistance; PD-L1 miR-34a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Arsenic Trioxide
  • Arsenicals / pharmacology
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • Base Sequence
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • HL-60 Cells
  • Humans
  • Interferon-gamma / metabolism
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Male
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Oligonucleotides, Antisense / metabolism
  • Oxides / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / metabolism
  • Sequence Alignment
  • Up-Regulation / drug effects


  • Antineoplastic Agents
  • Arsenicals
  • B7-H1 Antigen
  • CD274 protein, human
  • MIRN34 microRNA, human
  • MicroRNAs
  • Oligonucleotides, Antisense
  • Oxides
  • RNA, Small Interfering
  • Interferon-gamma
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • Arsenic Trioxide