Targeting uridine-cytidine kinase 2 induced cell cycle arrest through dual mechanism and could improve the immune response of hepatocellular carcinoma.
Hepatocellular carcinoma
Microenvironment
Pyrimidine metabolism
Secretory phenotype
Uridine–cytidine kinase 2
Journal
Cellular & molecular biology letters
ISSN: 1689-1392
Titre abrégé: Cell Mol Biol Lett
Pays: England
ID NLM: 9607427
Informations de publication
Date de publication:
26 Nov 2022
26 Nov 2022
Historique:
received:
16
06
2022
accepted:
03
11
2022
entrez:
29
11
2022
pubmed:
30
11
2022
medline:
2
12
2022
Statut:
epublish
Résumé
Pyrimidine metabolism is critical for tumour progression. Uridine-cytidine kinase 2 (UCK2), a key regulator of pyrimidine metabolism, is elevated during hepatocellular carcinoma (HCC) development and exhibits carcinogenic effects. However, the key mechanism of UCK2 promoting HCC and the therapeutic value of UCK2 are still undefined. The aim of this study is to investigate the potential of UCK2 as a therapeutic target for HCC. Gene expression matrices were obtained from public databases. RNA-seq, co-immunoprecipitation and RNA-binding protein immunoprecipitation were used to determine the mechanism of UCK2 promoting HCC. Immune cell infiltration level and immune-related functional scores were evaluated to assess the link between tumour microenvironment and UCK2. In HCC, the expression of UCK2 was upregulated in part by TGFβ1 stimulation. UCK2 promoted cell cycle progression of HCC by preventing the degradation of mTOR protein and maintaining the stability of PDPK1 mRNA. We also identified UCK2 as a novel RNA-binding protein. Downregulation of UCK2 induced cell cycle arrest and activated the TNFα/NFκB signalling pathway-related senescence-associated secretory phenotype to modify the tumour microenvironment. Additionally, UCK2 was a biomarker of the immunosuppressive microenvironment. Downregulated UCK2 induced a secretory phenotype, which could improve the microenvironment, and decreased UCK2 remodelling metabolism could lower the resistance of tumour cells to T-cell-mediated killing. Targeting UCK2 inhibits HCC progression and could improve the response to immunotherapy in patients with HCC. Our study suggests that UCK2 could be an ideal target for HCC.
Sections du résumé
BACKGROUND
BACKGROUND
Pyrimidine metabolism is critical for tumour progression. Uridine-cytidine kinase 2 (UCK2), a key regulator of pyrimidine metabolism, is elevated during hepatocellular carcinoma (HCC) development and exhibits carcinogenic effects. However, the key mechanism of UCK2 promoting HCC and the therapeutic value of UCK2 are still undefined. The aim of this study is to investigate the potential of UCK2 as a therapeutic target for HCC.
METHODS
METHODS
Gene expression matrices were obtained from public databases. RNA-seq, co-immunoprecipitation and RNA-binding protein immunoprecipitation were used to determine the mechanism of UCK2 promoting HCC. Immune cell infiltration level and immune-related functional scores were evaluated to assess the link between tumour microenvironment and UCK2.
RESULTS
RESULTS
In HCC, the expression of UCK2 was upregulated in part by TGFβ1 stimulation. UCK2 promoted cell cycle progression of HCC by preventing the degradation of mTOR protein and maintaining the stability of PDPK1 mRNA. We also identified UCK2 as a novel RNA-binding protein. Downregulation of UCK2 induced cell cycle arrest and activated the TNFα/NFκB signalling pathway-related senescence-associated secretory phenotype to modify the tumour microenvironment. Additionally, UCK2 was a biomarker of the immunosuppressive microenvironment. Downregulated UCK2 induced a secretory phenotype, which could improve the microenvironment, and decreased UCK2 remodelling metabolism could lower the resistance of tumour cells to T-cell-mediated killing.
CONCLUSIONS
CONCLUSIONS
Targeting UCK2 inhibits HCC progression and could improve the response to immunotherapy in patients with HCC. Our study suggests that UCK2 could be an ideal target for HCC.
Identifiants
pubmed: 36447138
doi: 10.1186/s11658-022-00403-y
pii: 10.1186/s11658-022-00403-y
pmc: PMC9707060
doi:
Substances chimiques
3-Phosphoinositide-Dependent Protein Kinases
EC 2.7.11.1
PDPK1 protein, human
EC 2.7.11.1
Pyrimidines
0
Uridine Kinase
EC 2.7.1.48
UCK2 protein, human
EC 2.7.1.48
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
105Subventions
Organisme : National Natural Science Foundation of China
ID : 81972724
Informations de copyright
© 2022. The Author(s).
Références
Cell Metab. 2019 Feb 5;29(2):399-416.e10
pubmed: 30449682
Theranostics. 2020 May 25;10(15):7002-7014
pubmed: 32550918
Front Immunol. 2020 Jul 08;11:1444
pubmed: 32733479
Nat Rev Gastroenterol Hepatol. 2021 May;18(5):293-313
pubmed: 33510460
Mol Cell. 2020 Jun 18;78(6):1019-1033
pubmed: 32559423
Cancer Discov. 2021 Jun;11(6):1524-1541
pubmed: 33589424
Nat Med. 2018 Oct;24(10):1550-1558
pubmed: 30127393
Hepatology. 2021 Jan;73 Suppl 1:4-13
pubmed: 32319693
Nat Commun. 2021 Jan 28;12(1):653
pubmed: 33510147
Ann Transl Med. 2021 Jul;9(14):1155
pubmed: 34430596
IUBMB Life. 2019 Jan;71(1):105-112
pubmed: 30304569
Science. 2018 Dec 21;362(6421):1416-1422
pubmed: 30573629
Bioinformatics. 2019 Oct 15;35(20):4200-4202
pubmed: 30903160
Cell. 2019 Oct 3;179(2):561-577.e22
pubmed: 31585088
Cancers (Basel). 2019 May 17;11(5):
pubmed: 31108873
Cancer Manag Res. 2018 Nov 26;10:6339-6355
pubmed: 30568496
Mol Carcinog. 2019 Apr;58(4):603-615
pubmed: 30556610
Trends Cancer. 2016 Nov;2(11):676-687
pubmed: 28741506
Oncogenesis. 2020 Dec 4;9(12):103
pubmed: 33277463
J Breast Cancer. 2017 Jun;20(2):132-141
pubmed: 28690649
Cancer Sci. 2019 Sep;110(9):2734-2747
pubmed: 31278886
Cancer Res. 2017 Feb 1;77(3):632-645
pubmed: 27872089
Neoplasia. 2019 Jun;21(6):591-601
pubmed: 31055200
Nucleosides Nucleotides Nucleic Acids. 2016 Dec;35(10-12):613-618
pubmed: 27906629
J Exp Med. 2016 Jan 11;213(1):35-51
pubmed: 26712805
Oncogene. 2020 Sep;39(38):6099-6112
pubmed: 32811980
Mol Pharmacol. 2001 May;59(5):1181-6
pubmed: 11306702
Biochim Biophys Acta. 2016 Sep;1862(9):1504-12
pubmed: 27239701
Mol Metab. 2020 May;35:100962
pubmed: 32244187
Leukemia. 2021 Apr;35(4):1023-1036
pubmed: 32770088
Sci Adv. 2016 May 27;2(5):e1600200
pubmed: 27386546
Mol Oncol. 2021 Dec;15(12):3242-3255
pubmed: 34137158