PMID- 32571994
OWN - NLM
STAT- MEDLINE
DCOM- 20210316
LR  - 20210316
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 8
IP  - 1
DP  - 2020 Jun
TI  - Targeting the coding sequence: opposing roles in regulating classical and 
      non-classical MHC class I molecules by miR-16 and miR-744.
LID - 10.1136/jitc-2019-000396 [doi]
LID - e000396
AB  - BACKGROUND: To control gene expression, microRNAs (miRNAs) are of key importance 
      and their deregulation is associated with the development and progression of 
      various cancer types. In this context, a discordant messenger RNA/protein 
      expression pointing to extensive post-transcriptional regulation of major 
      histocompatibility complex (MHC) class I molecules was already shown. However, 
      only a very limited number of miRNAs targeting these molecules have yet been 
      identified. Despite an increasing evidence of coding sequence (CDS)-located miRNA 
      binding sites, there exists so far, no detailed study of the interaction of 
      miRNAs with the CDS of MHC class I molecules. METHODS: Using an MS2-tethering 
      approach in combination with small RNA sequencing, a number of putative miRNAs 
      binding to the CDS of human leukocyte antigen (HLA)-G were identified. These 
      candidate miRNAs were extensively screened for their effects in the 
      HLA-G-positive JEG3 cell line. Due to the high sequence similarity between HLA-G 
      and classical MHC class I molecules, the impact of HLA-G candidate miRNAs on HLA 
      class I surface expression was also analyzed. The Cancer Genome Atlas data were 
      used to correlate candidate miRNAs and HLA class I gene expression. RESULTS: 
      Transfection of candidate miRNAs revealed that miR-744 significantly 
      downregulates HLA-G protein levels. In contrast, overexpression of the candidate 
      miRNAs miR-15, miR-16, and miR-424 sharing the same seed sequence resulted in an 
      unexpected upregulation of HLA-G. Comparable results were obtained for classical 
      MHC class I members after transfection of miRNA mimics into HEK293T cells. 
      Analyses of The Cancer Genome Atlas data sets for miRNA and MHC class I 
      expression further validated the results. CONCLUSIONS: Our data expand the 
      knowledge about MHC class I regulation and showed for the first time an 
      miRNA-dependent control of MHC class I antigens mediated by the CDS. CDS-located 
      miRNA binding sites could improve the general use of miRNA-based therapeutic 
      approaches as these sites are highly independent of structural variations (e.g. 
      mutations) in the gene body. Surprisingly, miR-16 family members promoted MHC 
      class I expression potentially in a gene activation-like mechanism.
CI  - (c) Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Friedrich, Michael
AU  - Friedrich M
AUID- ORCID: 0000-0001-8305-6189
AD  - Medical Immunology, Martin Luther University Halle Wittenberg, Halle, 
      Sachsen-Anhalt, Germany.
FAU - Vaxevanis, Christoforos K
AU  - Vaxevanis CK
AD  - Medical Immunology, Martin Luther University Halle Wittenberg, Halle, 
      Sachsen-Anhalt, Germany.
FAU - Biehl, Katharina
AU  - Biehl K
AD  - Medical Immunology, Martin Luther University Halle Wittenberg, Halle, 
      Sachsen-Anhalt, Germany.
FAU - Mueller, Anja
AU  - Mueller A
AD  - Medical Immunology, Martin Luther University Halle Wittenberg, Halle, 
      Sachsen-Anhalt, Germany.
FAU - Seliger, Barbara
AU  - Seliger B
AD  - Medical Immunology, Martin Luther University Halle Wittenberg, Halle, 
      Sachsen-Anhalt, Germany Barbara.Seliger@uk-halle.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (MIRN16 microRNA, human)
RN  - 0 (MIRN744 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Apoptosis
MH  - Cell Proliferation
MH  - *Gene Expression Regulation, Neoplastic
MH  - Histocompatibility Antigens Class I/classification/genetics/*immunology
MH  - Humans
MH  - MicroRNAs/*genetics
MH  - Neoplasms/genetics/*immunology/pathology
MH  - RNA, Messenger/genetics/*immunology
MH  - Tumor Cells, Cultured
PMC - PMC7307530
OTO - NOTNLM
OT  - HLA
OT  - molecular biology
OT  - oncology
COIS- Competing interests: None declared.
EDAT- 2020/06/24 06:00
MHDA- 2021/03/17 06:00
PMCR- 2020/06/21
CRDT- 2020/06/24 06:00
PHST- 2020/03/30 00:00 [accepted]
PHST- 2020/06/24 06:00 [entrez]
PHST- 2020/06/24 06:00 [pubmed]
PHST- 2021/03/17 06:00 [medline]
PHST- 2020/06/21 00:00 [pmc-release]
AID - jitc-2019-000396 [pii]
AID - 10.1136/jitc-2019-000396 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2020 Jun;8(1):e000396. doi: 10.1136/jitc-2019-000396.