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However, considering that human skin cancer is predominantly attributed to UV radiation from sunlight, additional investigations are needed to elucidate the role of P2RY6 in UVB\u2010induced skin carcinogenesis. Surprisingly, we found that P2ry6\u2010deficient mice exhibited marked promotion to UVB\u2010induced skin papilloma formation compared with wild\u2010type mice, suggesting its tumor\u2010suppressive role in UVB\u2010induced skin cancer. Additionally, a <jats:italic>P2ry6<\/jats:italic> gene knockout promoted skin hyperplasia induced by short\u2010term UVB irradiation, while UDP, the ligand of P2RY6, could inhibit the short\u2010term UVB\u2010induced increase of epiderma thickness in mouse skin. Furthermore, UVB irradiation could significantly upregulate P2RY6 expression in human and mouse skin cells. These results indicated that P2RY6 may play a crucial protective role in resisting the UVB\u2010induced formation of skin tumors. At the molecular level, the loss of the <jats:italic>P2RY6<\/jats:italic> gene inhibits the ubiquitination modification and expression of XPC after UVB irradiation in skin keratinocytes, resulting in the accumulation of CPDs (cyclobutane pyrimidine dimers). We have also demonstrated that P2RY6 deletion activates the PI3K\/AKT signaling pathway both in\u00a0vitro and in\u00a0vivo. The CPD accumulation and acute inflammatory response enhanced by the loss of the <jats:italic>P2RY6<\/jats:italic> gene can be reversed by an AKT inhibitor. These findings suggest that P2RY6 may act as a tumor suppressor in UVB\u2010induced skin cancer by regulating the PI3K\/AKT signaling pathway.<\/jats:p>","DOI":"10.1111\/cas.16378","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T10:38:29Z","timestamp":1729593509000},"page":"56-66","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp><i>P2RY6<\/i><\/scp> deletion promotes <scp>UVB<\/scp>\u2010induced skin carcinogenesis by activating the <scp>PI3K<\/scp>\/<scp>AKT<\/scp> signal pathway"],"prefix":"10.1111","volume":"116","author":[{"given":"Peng","family":"Xu","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences East China Normal University  Shanghai China"},{"name":"Department of Dermatology, Shanghai Tenth People's Hospital Tongji University School of Medicine  Shanghai 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