title: Feedback Activation of Basic Fibroblast Growth Factor Signaling via the Wnt/β-Catenin Pathway in Skin Fibroblasts.
abstract: 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, includingWnt2b,Wnt3,Wnt11,T-cell factor 7 (TCF7), andFrizzled 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-catenindelayed fibroblast cell migration even under bFGF stimulation. RNA sequencing analysis of β-cateninknock-down fibroblasts demonstrated that β-catenin positively regulated the transcription ofbFGFandFGF21.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.
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Haining Hospital of Traditional Chinese Medicine Haining, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Congcong
authors.initials: C
authors.lastname: Sun
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Wanhui
authors.initials: W
authors.lastname: Cai
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Sun
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Chi
authors.affiliation: School of Basic Medical Sciences, Xinxiang Medical University Xinxiang, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Basic Medical Sciences, Xinxiang Medical University Xinxiang, China.
authors.forename: Na
authors.initials: N
authors.lastname: Song
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Niu
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Shen
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Weitao
authors.initials: W
authors.lastname: Cong
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Yuanhu
authors.initials: Y
authors.lastname: Xuan
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Biotechnology Pharmaceutical Engineering, School of Pharmaceutical Sciences, Wenzhou Medical University Wenzhou, China.
authors.forename: Litai
authors.initials: L
authors.lastname: Jin
keywords: GSK3β; Wnt signaling pathway; bFGF; cell migration; transcriptome; β-catenin