The Wnt/β-Catenin Pathway Cross-Talks with STAT3 Signaling to Regulate Survival of Retinal Pigment Epithelium Cells

Wnt/β-catenin signaling is an essential pathway that regulates numerous cellular processes, including cell survival. The molecular mechanisms contributing to pro-survival Wnt signaling are mostly unknown. Signal transducer and activator of transcription proteins (STATs) are a well-described family of transcription factors. STAT3 induces expression of anti-apoptotic genes in many tissues and is a downstream mediator of protective growth factors and cytokines. In this study, we investigated whether pro-survival Wnt signaling is mediated by STAT3. The Wnt3a ligand activated Wnt signaling in the retinal pigment epithelium ARPE-19 cell line and significantly increased the viability of cells exposed to oxidative stress. Furthermore, Wnt3a increased STAT3 activation and nuclear translocation, as measured by an antibody against phosphorylated STAT3. Reducing STAT3 levels with siRNA eliminated Wnt3a-dependent protection from oxidative stress. Together, these data demonstrate a previously unknown link between Wnt3a-mediated activation of STAT3 and cell survival, and indicate cross-talk between two important pro-survival signaling pathways.Wnt/β-连环蛋白（Wnt/β-catenin）信号通路是调控包括细胞存活在内的多种细胞进程的关键通路。目前，介导促存活型Wnt信号转导的分子机制仍知之甚少。信号转导与转录激活因子（Signal transducer and activator of transcription proteins，STATs）是一类已被广泛研究的转录因子家族，其中STAT3可在多种组织中诱导抗凋亡基因的表达，同时作为保护性生长因子与细胞因子的下游介导因子发挥功能。本研究旨在探究促存活型Wnt信号转导是否由STAT3所介导。实验结果表明，Wnt3a配体可在视网膜色素上皮ARPE-19细胞系中激活Wnt信号通路，并显著提升氧化应激处理后细胞的存活率。此外，通过靶向磷酸化STAT3的抗体检测证实，Wnt3a可增强STAT3的活化与核转位过程。利用小干扰RNA（siRNA）敲低STAT3的表达水平后，Wnt3a介导的抗氧化应激保护作用被完全消除。综上，本研究数据揭示了Wnt3a介导的STAT3活化与细胞存活之间此前未被发现的关联，并表明两条重要的促存活信号通路之间存在交叉对话（cross-talk）。