Xu Peng, Wang Caibing, Xiang Wan, Liang Yiyi, Li Ying, Zhang Xilin, Guo Chunyuan, Liu Mingyao, Shi Yuling, Ye Xiyun, Dang Yongyan
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Department of Dermatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
J Invest Dermatol. 2022 Sep;142(9):2334-2342.e8. doi: 10.1016/j.jid.2022.02.017. Epub 2022 Mar 16.
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 signal‒regulated kinase kinase 1 and β-catenin were also impaired in P2ry6-knockout primary keratinocytes, tumor tissues, or MRS2578-treated HaCaT cells. Moreover, mutual promotion of the YAP and β-catenin signaling pathways was observed in normal skin cells treated with TPA, whereas P2ry6 deletion could inhibit their crosstalk by regulating MAPK/extracellular signal‒regulated kinase kinase 1. Thus, P2RY6 is a critical positive regulator of skin tumorigenesis through the modulation of the Hippo/YAP and Wnt/β-catenin signaling pathways.
P2RY6在皮肤角质形成细胞中高表达，但其在皮肤疾病中的功能尚不清楚。我们采用两步化学诱导法诱导小鼠皮肤肿瘤形成。运用多种体外和体内实验来探究P2RY6在皮肤肿瘤中的作用。我们报告称，与野生型小鼠相比，P2ry6基因缺陷型小鼠对7,12-二甲基苯并[a]蒽/12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的皮肤乳头瘤形成表现出显著抗性。与这些发现一致的是，在P2ry6基因敲除或用MRS2578（P2RY6拮抗剂）处理的小鼠中，对TPA的表皮增生反应受到抑制。由于P2ry6缺失导致的增生和肿瘤发生的显著减少与TPA诱导的角质形成细胞增殖和炎症反应的抑制有关。值得注意的是，P2ry6缺失以MST/LATS1依赖的方式阻止了TPA诱导的YAP核积累及其下游基因表达的增加。在TPA刺激下，P2ry6基因敲除的原代角质形成细胞、肿瘤组织或用MRS2578处理的HaCaT细胞中，MAPK/细胞外信号调节激酶激酶1和β-连环蛋白的增强激活也受到损害。此外，在用TPA处理的正常皮肤细胞中观察到YAP和β-连环蛋白信号通路的相互促进作用，而P2ry6缺失可通过调节MAPK/细胞外信号调节激酶激酶1来抑制它们的串扰。因此，P2RY6通过调节Hippo/YAP和Wnt/β-连环蛋白信号通路，是皮肤肿瘤发生的关键正调节因子。
