miR-181d/RBP2/NF-κB p65 Feedback Regulation Promotes Chronic Myeloid Leukemia Blast Crisis.
CML blast crisis
RBP2
cell proliferation
miR-181d
p65
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2021
2021
Historique:
received:
16
01
2021
accepted:
01
03
2021
entrez:
12
4
2021
pubmed:
13
4
2021
medline:
13
4
2021
Statut:
epublish
Résumé
Chronic myeloid leukemia (CML) is a malignant clonal proliferative disease. Once it progresses into the phase of blast crisis (CML-BP), the curative effect is poor, and the fatality rate is extremely high. Therefore, it is urgent to explore the molecular mechanisms of blast crisis and identify new therapeutic targets. The expression levels of miR-181d, RBP2 and NF-κB p65 were assessed in 42 newly diagnosed CML-CP patients and 15 CML-BP patients. Quantitative real-time PCR, Western blots, and cell proliferation assay were used to characterize the changes induced by overexpression or inhibition of miR-181d, RBP2 or p65. Luciferase reporter assay and ChIP assay was conducted to establish functional association between miR-181d, RBP2 and p65. Inhibition of miR-181d expression and its consequences in tumor growth was demonstrated We found that miR-181d was overexpressed in CML-BP, which promoted leukemia cell proliferation. Histone demethylase RBP2 was identified as a direct target of miR-181d which downregulated RBP2 expression. Moreover, RBP2 inhibited transcriptional expression of NF-κB subunit, p65 by binding to its promoter and demethylating the tri/dimethylated H3K4 region in the p65 promoter locus. In turn, p65 directly bound to miR-181d promoter and upregulated its expression. Therefore, RBP2 inhibition resulting from miR-181d overexpression led to p65 upregulation which further forwarded miR-181d expression. This miR-181d/RBP2/p65 feedback regulation caused sustained NF-κB activation, which contributed to the development of CML-BP. Taken together, the miR-181d/RBP2/p65 feedback regulation promoted CML-BP and miR-181d may serve as a potential therapeutic target of CML-BP.
Sections du résumé
BACKGROUND
BACKGROUND
Chronic myeloid leukemia (CML) is a malignant clonal proliferative disease. Once it progresses into the phase of blast crisis (CML-BP), the curative effect is poor, and the fatality rate is extremely high. Therefore, it is urgent to explore the molecular mechanisms of blast crisis and identify new therapeutic targets.
METHODS
METHODS
The expression levels of miR-181d, RBP2 and NF-κB p65 were assessed in 42 newly diagnosed CML-CP patients and 15 CML-BP patients. Quantitative real-time PCR, Western blots, and cell proliferation assay were used to characterize the changes induced by overexpression or inhibition of miR-181d, RBP2 or p65. Luciferase reporter assay and ChIP assay was conducted to establish functional association between miR-181d, RBP2 and p65. Inhibition of miR-181d expression and its consequences in tumor growth was demonstrated
RESULTS
RESULTS
We found that miR-181d was overexpressed in CML-BP, which promoted leukemia cell proliferation. Histone demethylase RBP2 was identified as a direct target of miR-181d which downregulated RBP2 expression. Moreover, RBP2 inhibited transcriptional expression of NF-κB subunit, p65 by binding to its promoter and demethylating the tri/dimethylated H3K4 region in the p65 promoter locus. In turn, p65 directly bound to miR-181d promoter and upregulated its expression. Therefore, RBP2 inhibition resulting from miR-181d overexpression led to p65 upregulation which further forwarded miR-181d expression. This miR-181d/RBP2/p65 feedback regulation caused sustained NF-κB activation, which contributed to the development of CML-BP.
CONCLUSIONS
CONCLUSIONS
Taken together, the miR-181d/RBP2/p65 feedback regulation promoted CML-BP and miR-181d may serve as a potential therapeutic target of CML-BP.
Identifiants
pubmed: 33842368
doi: 10.3389/fonc.2021.654411
pmc: PMC8027495
doi:
Types de publication
Journal Article
Langues
eng
Pagination
654411Informations de copyright
Copyright © 2021 Zhou, Yin, Zheng, Fu, Wang, Cui, Gao, Wang, Huang, Jia and Chen.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Int J Mol Sci. 2019 Dec 05;20(24):
pubmed: 31817512
Cell Signal. 2019 Nov;63:109360
pubmed: 31374292
Oncotarget. 2016 Oct 4;7(40):66287-66298
pubmed: 27563822
Blood. 2012 Jul 26;120(4):737-47
pubmed: 22653972
J Biol Chem. 2011 Nov 4;286(44):38768-38782
pubmed: 21896491
Nat Struct Mol Biol. 2008 Apr;15(4):419-21
pubmed: 18270511
Nucleic Acids Res. 2012 Jul;40(12):5201-14
pubmed: 22362744
Int J Cancer. 2009 Jul 15;125(2):308-17
pubmed: 19378338
Oncotarget. 2015 Jan 20;6(2):1249-61
pubmed: 25575817
J Exp Clin Cancer Res. 2019 Feb 6;38(1):55
pubmed: 30728051
Blood. 2014 May 22;123(21):3277-85
pubmed: 24637363
Mol Cancer. 2014 Apr 09;13:81
pubmed: 24716659
Tumour Biol. 2017 Apr;39(4):1010428317698364
pubmed: 28381166
J Invest Dermatol. 2016 Apr;136(4):847-858
pubmed: 26802933
Oncogene. 2007 Mar 8;26(11):1586-94
pubmed: 16953217
J Cell Physiol. 2020 May;235(5):4766-4777
pubmed: 31674024
Mol Cancer. 2011 Apr 18;10:41
pubmed: 21501493
Cell. 2007 Mar 23;128(6):1063-76
pubmed: 17320161
Oncogene. 2015 Jun;34(25):3226-39
pubmed: 25174404
Cell. 2010 Mar 5;140(5):652-65
pubmed: 20211135
Blood. 2010 Mar 4;115(9):1768-78
pubmed: 20029046
Leukemia. 2006 Jan;20(1):61-7
pubmed: 16270044
Eur Rev Med Pharmacol Sci. 2019 Oct;23(20):8861-8869
pubmed: 31696473
Br J Pharmacol. 2010 Aug;160(7):1577-9
pubmed: 20649561
Blood. 2005 Jun 1;105(11):4163-9
pubmed: 15687234
Genes Dev. 2019 Dec 1;33(23-24):1718-1738
pubmed: 31727771
Cancer Cell. 2010 Apr 13;17(4):333-47
pubmed: 20385359
Ann Hematol. 2009 Apr;88(4):333-40
pubmed: 18781299
Cell Rep. 2016 Apr 12;15(2):288-99
pubmed: 27050510
Annu Rev Genet. 2018 Nov 23;52:21-41
pubmed: 30160987
Exp Mol Med. 2016 Jun 10;48:e238
pubmed: 27282106
J Clin Invest. 2013 Dec;123(12):5231-46
pubmed: 24200691
Lancet. 2015 Apr 11;385(9976):1447-59
pubmed: 25484026
J Hematol Oncol. 2009 Jul 14;2:28
pubmed: 19602237
PLoS Genet. 2012;8(8):e1002855
pubmed: 22916024
Trends Mol Med. 2006 Dec;12(12):580-7
pubmed: 17071139
Am J Physiol Lung Cell Mol Physiol. 2019 May 1;316(5):L918-L933
pubmed: 30628487
Mol Pharmacol. 2010 Nov;78(5):811-7
pubmed: 20693279
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):46-51
pubmed: 20080798
J Clin Invest. 2010 Jul;120(7):2254-64
pubmed: 20592475