P2RY6 deletion promotes UVB-induced skin carcinogenesis by activating the PI3K/AKT signal pathway.

IF 5.7 2区 医学 Q1 Medicine Cancer Science Pub Date : 2024-10-22 DOI:10.1111/cas.16378
Peng Xu, Tanglin Liu, Zile Yang, Kai Zang, Xiaoxuan Gao, Yuling Shi, Xiyun Ye, Yongyan Dang
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Abstract

Our previous research has demonstrated that P2RY6 functions as an oncogene in DMBA/TPA-induced two-stage chemical skin carcinogenesis in mice. 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-induced skin carcinogenesis. Surprisingly, we found that P2ry6-deficient mice exhibited marked promotion to UVB-induced skin papilloma formation compared with wild-type mice, suggesting its tumor-suppressive role in UVB-induced skin cancer. Additionally, a P2ry6 gene knockout promoted skin hyperplasia induced by short-term UVB irradiation, while UDP, the ligand of P2RY6, could inhibit the short-term UVB-induced 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-induced formation of skin tumors. At the molecular level, the loss of the P2RY6 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 vitro and in vivo. The CPD accumulation and acute inflammatory response enhanced by the loss of the P2RY6 gene can be reversed by an AKT inhibitor. These findings suggest that P2RY6 may act as a tumor suppressor in UVB-induced skin cancer by regulating the PI3K/AKT signaling pathway.

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P2RY6 基因缺失可通过激活 PI3K/AKT 信号通路促进紫外线诱导的皮肤癌发生。
我们之前的研究表明,P2RY6 在 DMBA/TPA 诱导的小鼠两阶段化学皮肤癌变中发挥着癌基因的作用。然而,考虑到人类皮肤癌主要归因于日光中的紫外线辐射,我们需要进行更多的研究来阐明 P2RY6 在紫外线诱导的皮肤癌中的作用。令人惊讶的是,我们发现与野生型小鼠相比,P2ry6 缺陷小鼠对紫外线诱导的皮肤乳头状瘤的形成有明显的促进作用,这表明它在紫外线诱导的皮肤癌中具有抑制肿瘤的作用。此外,P2ry6 基因敲除能促进短期 UVB 照射诱导的皮肤增生,而 P2RY6 的配体 UDP 能抑制短期 UVB 诱导的小鼠皮肤表皮厚度的增加。此外,UVB 照射能显著上调 P2RY6 在人和小鼠皮肤细胞中的表达。这些结果表明,P2RY6可能在抵御紫外线诱导的皮肤肿瘤形成过程中发挥着重要的保护作用。在分子水平上,P2RY6 基因缺失会抑制皮肤角质细胞在紫外线照射后 XPC 的泛素化修饰和表达,导致 CPD(环丁烷嘧啶二聚体)的积累。我们还证实,P2RY6 基因缺失可激活体外和体内的 PI3K/AKT 信号通路。AKT 抑制剂可逆转因 P2RY6 基因缺失而增强的 CPD 积累和急性炎症反应。这些研究结果表明,P2RY6可通过调节PI3K/AKT信号通路,在紫外线诱导的皮肤癌中起到抑制肿瘤的作用。
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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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