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J Dermatol Sci. 2016 Apr;82(1):28-37. doi: 10.1016/j.jdermsci.2016.01.003. Epub 2016 Jan 7.

The activation of the NF-κB-JNK pathway is independent of the PI3K-Rac1-JNK pathway involved in the bFGF-regulated human fibroblast cell migration.

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School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou 325000, China.
Ningbo First Hospital, Ningbo 315000, China.
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Institute of neuroscience, Department of histology and embryology, Wenzhou Medical University, Wenzhou 325000, China. Electronic address:
School of Pharmaceutical Sciences, Key Laboratory of Biotechnology Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou 325000, China. Electronic address:



Skin wound healing is a complex process that repairs multiple organ-tissues. Fibroblasts are key players of skin cells, whose migration is important during wound healing process. bFGF has shown a great efficacy to promote cell migration, but the precise mechanism by which bFGF regulates cell migration remains elusive.


The aim of this study was to find bFGF-regulated gene pools and further identify target molecules that participated in human fibroblast cell migration.


Skin primary fibroblasts and rat skin wound model were used to demonstrate the novel mechanism of bFGF regulating cell migration to accelerate wound healing. Cell migration was determined using the wound healing scratch assay. The differentially expressed genes and numerous biochemical pathways after bFGF treatment were identified by RNA-Seq analysis, and differentially expressed genes were further verified by qRT-PCR. siRNA duplex target to interfering the expression of PI3-kinase (p110α) was transformed into NIH/3T3 cells. Western blotting analysis was used to determine marker protein expressions. The invasive activity of fibroblasts was measured using 3D spheroid cell invasion assay.


RNA-Seq analysis identified numerous biochemical pathways including the NF-κB pathway under the control of FGF signaling. bFGF negatively regulates the phosphorylation of IκB-α, the most well studied NF-κB signaling regulator while bFGF induces JNK phosphorylation. Application of Bay11-7082, a representative NF-κB inhibitor promoted cell migration, invasion and enhanced the JNKs phosphorylation. However, inhibition of JNKs blocked cell migration when NF-κB is inhibited. Moreover, application of the PI3K inhibitor LY294002 together with Bay11-7082 maintained normal cell migration and knocking-down PI3K (p110α) by a specific siRNA inhibited JNKs phosphorylation while maintaining normal IκBα phosphorylation, indicating that PI3K and NF-κB signaling independently regulate JNKs activation. In addition, administration of bFGF or Bay11-7082 promoted rat skin wound repair and accelerated the invasion of fibroblasts.


This study sheds light on the mode of action of bFGF and identifies that the NF-κB-JNKs pathway is independent of the PI3K-JNKs pathway to accelerate fibroblast migration. In addition, bFGF and the relief of inflammation could be a favorable therapeutic approach for skin wound healing.


Cell migration; JNK; NF-κB; Transcriptome; bFGF

[Indexed for MEDLINE]

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