Feedback Activation of Basic Fibroblast Growth Factor Signaling via the Wnt/β-Catenin Pathway in Skin Fibroblasts.
Feedback Activation of Basic Fibroblast Growth Factor Signaling via the Wnt/β-Catenin Pathway in Skin Fibroblasts.
复制标题
通过皮肤成纤维细胞中的 Wnt/β-连环蛋白途径反馈激活碱性成纤维细胞生长因子信号传导
DOI：
10.3389/fphar.2017.00032
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发表时间：
2017
影响因子：
5.6
通讯作者：
Jin L
中科院分区：
文献类型：
--
作者：
Wang X;Zhu Y;Sun C;Wang T;Shen Y;Cai W;Sun J;Chi L;Wang H;Song N;Niu C;Shen J;Cong W;Zhu Z;Xuan Y;Li X;Jin L
皮肤伤口愈合是一个复杂的过程，需要许多细胞类型的协调行为，特别是成纤维细胞的增殖和迁移。碱性成纤维细胞生长因子（bFGF）是FGF家族的一员，可促进成纤维细胞迁移，但其潜在的分子机制仍不清楚。目前的RNA测序研究表明，几个典型的Wnt途径基因，包括Wnt 2b，Wnt 3，Wnt 11，T细胞因子7（TCF 7），和卷曲8（FZD 8）的表达水平通过bFGF刺激成纤维细胞进行修改。酶联免疫吸附试验（ELISA）分析也表明，Wnt途径激活bFGF处理。此外，用氯化锂或IWR-1（Wnt信号通路的诱导剂和抑制剂）处理成纤维细胞，分别促进和抑制细胞迁移。此外，细胞溶质糖原合成酶激酶3 β丝氨酸9磷酸化（pGSK 3 β Ser 9）和细胞核β-连环蛋白的水平在暴露于bFGF后增加。分子生物学检测表明，磷脂酰肌醇3-激酶（PI 3 K）信号通过激活c-Jun N-末端激酶（JNK）激活GSK 3 β/β-catenin/Wnt信号通路，提示PI 3 K和JNK作用于β-catenin的上游。相反，β-连环蛋白的敲低延迟成纤维细胞迁移，即使在bFGF刺激下。对β-catenin敲低的成纤维细胞的RNA测序分析表明，β-catenin正调控bFGF和FGF 21的转录。此外，FGF 21处理激活AKT和JNK，并加速成纤维细胞迁移到与bFGF相似的程度。ELISA分析表明bFGF和FGF 21均为自分泌因子，受Wnt信号通路刺激因子的调节。综上所述，我们的分析确定了bFGF（FGF 21）和Wnt信号之间的反馈调节环，通过β-连环蛋白在皮肤成纤维细胞中起作用。
Skin wound healing is a complex process requiring the coordinated behavior of many cell types, especially in the proliferation and migration of fibroblasts. Basic fibroblast growth factor (bFGF) is a member of the FGF family that promotes fibroblast migration, but the underlying molecular mechanism remains elusive. The present RNA sequencing study showed that the expression levels of several canonical Wnt pathway genes, including Wnt2b, Wnt3, Wnt11, T-cell factor 7 (TCF7), and Frizzled 8 (FZD8) were modified by bFGF stimulation in fibroblasts. Enzyme-linked immunosorbent assay (ELISA) analysis also showed that Wnt pathway was activated under bFGF treatment. Furthermore, treatment of fibroblasts with lithium chloride or IWR-1, an inducer and inhibitor of the Wnt signaling pathway, respectively, promoted and inhibited cell migration. Also, levels of cytosolic glycogen synthase kinase 3 beta phosphorylated at serine9 (pGSK3β Ser9) and nuclear β-catenin were increased upon exposure to bFGF. Molecular and biochemical assays indicated that phosphoinositide 3-kinase (PI3K) signaling activated the GSK3β/β-catenin/Wnt signaling pathway via activation of c-Jun N-terminal kinase (JNK), suggesting that PI3K and JNK act at the upstream of β-catenin. In contrast, knock-down of β-catenin delayed fibroblast cell migration even under bFGF stimulation. RNA sequencing analysis of β-catenin knock-down fibroblasts demonstrated that β-catenin positively regulated the transcription of bFGF and FGF21. Moreover, FGF21 treatment activated AKT and JNK, and accelerated fibroblast migration to a similar extent as bFGF does. In addition, ELISA analysis demonstrated that both of bFGF and FGF21 were auto secretion factor and be regulated by Wnt pathway stimulators. Taken together, our analyses define a feedback regulatory loop between bFGF (FGF21) and Wnt signaling acting through β-catenin in skin fibroblasts.