CXCR2 expression during melanoma tumorigenesis controls transcriptional programs that facilitate tumor growth.
CXCR2
Genetic mouse models
Genomic analysis
Melanoma
Tumor immune microenvironment
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
03 06 2023
03 06 2023
Historique:
received:
03
03
2023
accepted:
16
05
2023
medline:
5
6
2023
pubmed:
4
6
2023
entrez:
3
6
2023
Statut:
epublish
Résumé
Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established. To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven Braf Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1, a key tumor suppressive transcription factor, was the only gene significantly induced with a log Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.
Sections du résumé
BACKGROUND
Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established.
METHODS
To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven Braf
RESULTS
Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1, a key tumor suppressive transcription factor, was the only gene significantly induced with a log
CONCLUSIONS
Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.
Identifiants
pubmed: 37270599
doi: 10.1186/s12943-023-01789-9
pii: 10.1186/s12943-023-01789-9
pmc: PMC10239119
doi:
Substances chimiques
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Receptors, Interleukin-8B
0
Cxcr2 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
92Subventions
Organisme : NCI NIH HHS
ID : R21 CA116022
Pays : United States
Organisme : NIH HHS
ID : S10 OD023475
Pays : United States
Organisme : BLRD VA
ID : IK6 BX005225
Pays : United States
Organisme : NIH HHS
ID : S10 OD016355
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA119925
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA240901
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK058404
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA021765
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009582
Pays : United States
Organisme : BLRD VA
ID : I01 BX002301
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA217450
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA068485
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA116021
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA272875
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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