Xu Peng, Dang Yongyan, Wang Luyang, Liu Xia, Ren Xiaolin, Gu Jun, Liu Mingyao, Dai Xing, Ye Xiyun
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai 200241, China.
Department of Dermatology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.
Cancer Lett. 2016 Dec 28;383(2):161-170. doi: 10.1016/j.canlet.2016.09.005. Epub 2016 Sep 30.
Lgr4 is a member of the leucine-rich, G protein-coupled receptor family of proteins, and has recently been shown to augment Wnt/β-catenin signaling via binding to Wnt agonists R-spondins. It plays an important role in skin development, but its involvement in skin tumorigenesis is unclear. Here, we report that mice deficient for Lgr4 are resistant to 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced keratinocyte proliferation and papilloma formation. We show that TPA treatment activates MEK1, ERK1/2 and downstream effector AP-1 in wild-type (WT) epidermal cells and mice, but not in cells or mice where Lgr4 is depleted. Wnt/β-catenin signaling is also dramatically activated by TPA treatment, and this activation is abolished when Lgr4 is deleted. We provide evidences that blocking both MEK1/ERK1/2 and Wnt/β-catenin pathways prevents TPA-induced increase in the expression of Ccnd1 (cyclin D1), a known Wnt/β-catenin target gene, and that the activation of MEK1/ERK1/2 pathway lies upstream of Wnt/β-catenin signal pathway. Collectively, our findings identify Lgr4 as a critical positive factor for skin tumorigenesis by mediating the activation of MEK1/ERK1/2 and Wnt/β-catenin pathways.
Lgr4是富含亮氨酸的G蛋白偶联受体蛋白家族的成员，最近研究表明它可通过与Wnt激动剂R-spondins结合来增强Wnt/β-连环蛋白信号传导。它在皮肤发育中起重要作用，但其在皮肤肿瘤发生中的作用尚不清楚。在此，我们报告Lgr4基因缺陷的小鼠对12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的角质形成细胞增殖和乳头状瘤形成具有抗性。我们发现TPA处理可激活野生型（WT）表皮细胞和小鼠中的MEK1、ERK1/2及下游效应因子AP-1，但在Lgr4缺失的细胞或小鼠中则不然。TPA处理也可显著激活Wnt/β-连环蛋白信号传导，而当Lgr4缺失时这种激活作用消失。我们提供的证据表明，阻断MEK1/ERK1/2和Wnt/β-连环蛋白途径可阻止TPA诱导的已知Wnt/β-连环蛋白靶基因Ccnd1（细胞周期蛋白D1）表达增加，且MEK1/ERK1/2途径的激活位于Wnt/β-连环蛋白信号途径的上游。总的来说，我们的研究结果表明Lgr4通过介导MEK1/ERK1/2和Wnt/β-连环蛋白途径的激活，是皮肤肿瘤发生的关键正向因子。
