In:
Frontiers in Oncology, Frontiers Media SA, Vol. 13 ( 2023-6-7)
Kurzfassung:
Melanoma is a common and aggressive type of skin cancer with rising incidence rate globally. Gender is one of the determining factors, and overall males have a higher risk of developing melanoma as well as worse prognosis. Emerging evidence show that GPR68, a G protein-coupled receptor that is sensitive to acid and mechanical stimulations for cellular microenvironment, plays an important role in tumor biology. However, whether GPR68 is involved in gender-dependent regulation of tumor growth is unclear. Methods We established a syngeneic melanoma model in Gpr68 -deficient mice and investigated tumor growth in males and females. The GPR68 activation-induced cellular responses of melanocytes, including intracellular calcium dynamics, proliferation and migration were measured. The landscape of tumor-infiltrating immune cells were analyzed by flow cytometry and the expression various cytokines were checked by qRT-PCR. Results GPR68 is required for melanoma growth in males but dispensable in females. GPR68 is expressed and functional in B16-F10 melanocytes, but the activity of the receptor does not directly contribute to proliferation and migration of the cells. GPR68 inhibits infiltration of CD45 + lymphocytes, CD8 + T cells and NK cells in melanoma in male mice, but has no apparent effect in females. Furthermore, GPR68 functionally inhibits the expression of IFNγ in the tumor infiltrating CD8 + T cells and NK cells as well as the inflammatory cytokine expression in the spleen in male mice but not in females. Our results show the gender-dependent modulatory effect of GPR68 on tumor-infiltrating immune cells and their tumor-killing capacity. Discussion GPR68 is sensor for acid and mechanical stimulations, which are two important factors in the microenvironment associated with tumor growth and metastasis. Our results suggest a prominent role of the receptor molecules in tumor biology in a gender-dependent manner. Since GPCRs are more feasible to develop small molecule drugs compared to transcription factors, our study demonstrates the potential of GPR68 as a novel druggable therapeutic target for melanoma in male patients.
Materialart:
Online-Ressource
ISSN:
2234-943X
DOI:
10.3389/fonc.2023.1202750
DOI:
10.3389/fonc.2023.1202750.s001
DOI:
10.3389/fonc.2023.1202750.s002
DOI:
10.3389/fonc.2023.1202750.s003
DOI:
10.3389/fonc.2023.1202750.s004
DOI:
10.3389/fonc.2023.1202750.s005
DOI:
10.3389/fonc.2023.1202750.s006
DOI:
10.3389/fonc.2023.1202750.s007
DOI:
10.3389/fonc.2023.1202750.s008
DOI:
10.3389/fonc.2023.1202750.s009
DOI:
10.3389/fonc.2023.1202750.s010
DOI:
10.3389/fonc.2023.1202750.s011
DOI:
10.3389/fonc.2023.1202750.s012
Sprache:
Unbekannt
Verlag:
Frontiers Media SA
Publikationsdatum:
2023
ZDB Id:
2649216-7
