Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration.
Keloids, partially considered as benign tumors, represent the most extreme example of cutaneous scarring that uniquely afflicts humans as a pathological response to wound healing. It is characterized by excessive deposition of collagen and other extracellular matrix components by dermal fibroblasts. Upon cutaneous injury, cocktails of chemokines, cytokines and growth factors are secreted temporally and spatially to direct appropriate responses from neutrophils, macrophages, keratinocytes and fibroblasts to facilitate normal wound healing. Signal transducer and activator of transcription 3 (Stat3) is an oncogene and a latent transcription factor activated by various cytokines and growth factors. We investigated the possible role of Stat3 in keloid scar pathogenesis by examining skin tissue and cultured fibroblasts from keloid-scarred patients. We observed enhanced expression and phosphorylation of Stat3 in keloid scar tissue, and in cultured keloid fibroblasts (KFs) in vitro. Increased activation of Janus kinase (Jak)2, but not Jak1, was detected in KFs, and suppression of Jak2 by its inhibitor repressed Stat3 Y705 phosphorylation. Inhibition of Stat3 expression and phosphorylation by short interfering RNA or Cucurbitacin I resulted in the loss of collagen production, impaired proliferation and delayed cell migration in KFs. We show, for the first time, a role of Stat3 in keloid pathogenesis. Inhibitors of Stat3 may be useful therapeutic strategies for the prospective treatment of keloid scars.
Lim
C P
CP
Institute of Molecular and Cell Biology, Proteos, Singapore, Singapore.
Phan
T-T
TT
Lim
I J
IJ
Cao
X
X
D001483:Base Sequence; D002455:Cell Division / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen / Q000096:biosynthesis*; D017931:DNA Primers; D006801:Humans; D007627:Keloid / Q000503:physiopathology*; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000293:injuries* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D017931:DNA Primers; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D003094:Collagen