P2RY6 Has a Critical Role in Mouse Skin Carcinogenesis by Regulating the YAP and ß-Catenin Signaling Pathways.
J Invest Dermatol
; 142(9): 2334-2342.e8, 2022 09.
Article
em En
| MEDLINE
| ID: mdl-35304248
ABSTRACT
P2RY6 is highly expressed in skin keratinocytes, but its function in skin diseases is unclear. We use a two-step chemical induction method to induce mouse skin tumor formation. Multiple in vitro and in vivo assays were used to explore the role of P2RY6 in skin tumors. We report that P2ry6-deficient mice exhibit marked resistance to 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin papilloma formation compared with wild-type mice. Consistent with these findings, epidermal hyperplasia in response to TPA was suppressed in the P2ry6-knockout or MRS2578 (P2RY6 antagonist)-treated mice. The dramatic decrease in hyperplasia and tumorigenesis due to P2ry6 disruption was associated with the suppression of TPA-induced keratinocyte proliferation and inflammatory reactions. Notably, P2ry6 deletion prevented the TPA-induced increase in YAP nuclear accumulation and its downstream gene expression in an MST/LATS1-dependent manner. On TPA stimulation, enhanced activation of MAPK/extracellular signalâregulated kinase kinase 1 and ß-catenin were also impaired in P2ry6-knockout primary keratinocytes, tumor tissues, or MRS2578-treated HaCaT cells. Moreover, mutual promotion of the YAP and ß-catenin signaling pathways was observed in normal skin cells treated with TPA, whereas P2ry6 deletion could inhibit their crosstalk by regulating MAPK/extracellular signalâregulated kinase kinase 1. Thus, P2RY6 is a critical positive regulator of skin tumorigenesis through the modulation of the Hippo/YAP and Wnt/ß-catenin signaling pathways.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
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Receptores Purinérgicos P2
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Via de Sinalização Wnt
Limite:
Animals
Idioma:
En
Revista:
J Invest Dermatol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China