UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer.
Mesenchymal
Molecular subtypes
Ovarian cancer
Tumor microenvironment
UGDH
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
19 Oct 2023
19 Oct 2023
Historique:
received:
28
04
2023
accepted:
02
09
2023
medline:
23
10
2023
pubmed:
20
10
2023
entrez:
20
10
2023
Statut:
epublish
Résumé
Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH). Immunohistochemistry was used to characterize UGDH expression in histological and molecular subtypes of EOC. EOC cell lines were subtyped according to the molecular subtypes and the functional effects of modulating UGDH expression in vitro and in vivo in C1/Mesenchymal and C4/Differentiated subtype cell lines was examined. High UGDH expression was observed in high-grade serous ovarian cancers and a distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype. High UGDH was associated with a poor prognosis in the C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Knockdown of UGDH in the C1/mesenchymal molecular subtype reduced spheroid formation and viability and reduced the CD133 + /ALDH These data show that modulation of UGDH expression in ovarian cancer reveals distinct roles for UGDH in the C1/Mesenchymal and C4/Differentiated molecular subtypes of EOC, influencing the tumor microenvironmental composition. UGDH is a strong potential therapeutic target in TICs, for the treatment of EOC, particularly in patients with the mesenchymal molecular subtype.
Sections du résumé
BACKGROUND
BACKGROUND
Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH).
METHODS
METHODS
Immunohistochemistry was used to characterize UGDH expression in histological and molecular subtypes of EOC. EOC cell lines were subtyped according to the molecular subtypes and the functional effects of modulating UGDH expression in vitro and in vivo in C1/Mesenchymal and C4/Differentiated subtype cell lines was examined.
RESULTS
RESULTS
High UGDH expression was observed in high-grade serous ovarian cancers and a distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype. High UGDH was associated with a poor prognosis in the C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Knockdown of UGDH in the C1/mesenchymal molecular subtype reduced spheroid formation and viability and reduced the CD133 + /ALDH
CONCLUSIONS
CONCLUSIONS
These data show that modulation of UGDH expression in ovarian cancer reveals distinct roles for UGDH in the C1/Mesenchymal and C4/Differentiated molecular subtypes of EOC, influencing the tumor microenvironmental composition. UGDH is a strong potential therapeutic target in TICs, for the treatment of EOC, particularly in patients with the mesenchymal molecular subtype.
Identifiants
pubmed: 37858159
doi: 10.1186/s13046-023-02820-z
pii: 10.1186/s13046-023-02820-z
pmc: PMC10585874
doi:
Substances chimiques
RNA, Small Interfering
0
UGDH protein, human
EC 1.1.1.22
Uridine Diphosphate Glucose Dehydrogenase
EC 1.1.1.22
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
270Subventions
Organisme : NIH HHS
ID : HHSN261200800001E
Pays : United States
Organisme : NCI NIH HHS
ID : ZIA BC011054
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800001C
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011054
Pays : United States
Organisme : NIH HHS
ID : HHSN261201800001I
Pays : United States
Informations de copyright
© 2023. Italian National Cancer Institute ‘Regina Elena’.
Références
Pleura Peritoneum. 2016 Jun 1;1(2):79-89
pubmed: 30911611
Nat Methods. 2013 Apr;10(4):325-7
pubmed: 23435259
CA Cancer J Clin. 2023 Jan;73(1):17-48
pubmed: 36633525
Front Oncol. 2013 Sep 25;3:256
pubmed: 24093089
Am J Pathol. 2010 Sep;177(3):1053-64
pubmed: 20651229
Genomics Proteomics Bioinformatics. 2021 Feb;19(1):108-122
pubmed: 33610792
Int J Biol Sci. 2019 Jan 1;15(2):341-350
pubmed: 30745825
J Cell Physiol. 2011 Mar;226(3):749-61
pubmed: 20717929
Bioinformatics. 2012 Aug 15;28(16):2184-5
pubmed: 22743226
Breast Cancer Res Treat. 2021 Jan;185(2):293-305
pubmed: 33073304
J Vis Exp. 2015 Feb 18;(96):
pubmed: 25742116
Trends Immunol. 2017 Nov;38(11):858-871
pubmed: 28684207
Gynecol Oncol. 2018 Aug;150(2):227-232
pubmed: 29925470
Science. 2015 Jan 23;347(6220):1260419
pubmed: 25613900
Int J Gynaecol Obstet. 2021 Oct;155 Suppl 1:61-85
pubmed: 34669199
EMBO Mol Med. 2013 Jul;5(7):1051-66
pubmed: 23666744
Adv Exp Med Biol. 2020;1245:67-83
pubmed: 32266653
Gynecol Oncol. 2019 Apr;153(1):127-134
pubmed: 30686551
Cancers (Basel). 2020 Jun 21;12(6):
pubmed: 32575908
Nature. 2019 Jul;571(7763):127-131
pubmed: 31243371
J Transl Med. 2022 May 31;20(1):246
pubmed: 35641987
J Natl Cancer Inst. 2015 Apr 13;107(7):
pubmed: 25868577
Nature. 2011 Jun 29;474(7353):609-15
pubmed: 21720365
Oncogene. 2018 May;37(20):2615-2629
pubmed: 29479058
Biomolecules. 2021 Feb 09;11(2):
pubmed: 33572239
Oncotarget. 2017 Apr 4;8(14):23862-23870
pubmed: 27852043
Front Immunol. 2020 Mar 24;11:512
pubmed: 32265939
Clin Exp Med. 2023 Sep;23(5):1359-1373
pubmed: 36173487
Adv Sci (Weinh). 2020 Oct 11;7(23):2001914
pubmed: 33304752
Oncogene. 2018 Sep;37(37):5127-5135
pubmed: 29789717
Int J Mol Sci. 2021 May 11;22(10):
pubmed: 34064635
Gynecol Oncol. 2015 Dec;139(3):394-400
pubmed: 26348314
Clin Exp Metastasis. 2022 Apr;39(2):291-301
pubmed: 34822024
SLAS Discov. 2017 Jun;22(5):525-536
pubmed: 28277887
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Int J Biochem Cell Biol. 2019 Apr;109:90-104
pubmed: 30743057
Arthritis Res Ther. 2014 Dec 03;16(6):484
pubmed: 25465897
Cancers (Basel). 2021 Jan 12;13(2):
pubmed: 33445692
Nat Rev Endocrinol. 2015 Sep;11(9):535-46
pubmed: 26215259
Cancer. 2019 Dec 15;125 Suppl 24:4609-4615
pubmed: 31967680
Oncotarget. 2019 Feb 22;10(16):1542-1543
pubmed: 30899420
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
Gynecol Oncol. 2017 Dec;147(3):503-508
pubmed: 28964622
J Cell Mol Med. 2020 Oct;24(20):11883-11902
pubmed: 32893977
Am J Transl Res. 2017 Feb 15;9(2):301-315
pubmed: 28337261
J Dev Biol. 2019 Apr 08;7(2):
pubmed: 30965570
J Pathol. 2015 Jul;236(3):272-7
pubmed: 25810134
Genes Dis. 2021 Sep 17;9(3):717-730
pubmed: 35782977
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
BMC Bioinformatics. 2011 Aug 04;12:323
pubmed: 21816040
Exp Cell Res. 2010 Oct 15;316(17):2893-902
pubmed: 20691680
Methods Enzymol. 2019;629:151-176
pubmed: 31727238
Klin Lab Diagn. 2021 May 23;66(5):297-303
pubmed: 34047516
Oncol Lett. 2018 Feb;15(2):2611-2618
pubmed: 29434981
Gynecol Oncol. 2009 Apr;113(1):143-8
pubmed: 19135710
Horm Cancer. 2016 Aug;7(4):260-71
pubmed: 27307252
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Br J Cancer. 2016 Feb 16;114(4):417-26
pubmed: 26882065
Front Oncol. 2022 Mar 17;12:762820
pubmed: 35372040
Cancer Res. 2009 Mar 15;69(6):2332-9
pubmed: 19244115
BMC Bioinformatics. 2013 Jan 16;14:7
pubmed: 23323831
Pathology. 2013 Jan;45(1):49-54
pubmed: 23222243
Cancer Res. 2017 Dec 15;77(24):6927-6940
pubmed: 29074539
Cancer Lett. 2020 Nov 1;492:21-30
pubmed: 32768525
Oncotarget. 2022 Feb 14;13:332-346
pubmed: 35178190
Biomed Res. 2019;40(1):17-27
pubmed: 30787260
Arch Pathol Lab Med. 1985 Aug;109(8):716-21
pubmed: 3893381
Curr Med Chem. 2020;27(34):5675-5715
pubmed: 31419925
Front Oncol. 2021 Jan 15;10:604084
pubmed: 33520713
Clin Cancer Res. 2008 Aug 15;14(16):5198-208
pubmed: 18698038
Gynecol Oncol. 2016 Aug;142(2):332-40
pubmed: 27235858
Oncogene. 2020 Apr;39(15):3089-3101
pubmed: 31308490