C/EBPγ Regulates Wound Repair and EGF Receptor Signaling

We aimed at identifying novel regulators of skin wound healing (WH), in an epidermal scratch WH assay, by a small interfering RNA (siRNA) silencing approach. Several transcription factors have been previously reported to affect wound repair. We here show that gene silencing of the transcription factor CAAT enhancer-binding protein gamma (C/EBP gamma), STAT3, REL, RELA, RELB, SP1, and NFkB impaired WH in vitro, in keratinocytes, whereas E2F and CREBBP silencing accelerated the WH process. We further characterized C/EBP gamma, as its silencing yielded the maximal impairment (52.2 +/- 12.5%) of scratch wounding (SW). We found that C/EBP-gamma silencing inhibited both EGF- and serum-induced keratinocyte migration, whereas C/EBP gamma overexpression enhanced cell migration to EGF and to serum via the EGFR. Further, C/EBP gamma silencing impaired scratch-induced Y1068 and Y1173 EGFR phosphorylation, as well as Y118 paxillin phosphorylation, key molecules regulating cell migration and epidermal WH. Moreover, C/EBP gamma levels were induced in keratinocytes, following both SW and EGF stimulation. C/EBP gamma siRNA silencing in vivo impaired WH at 3, 5, 7, and 14 days following excisional wounding in mice inhibited both re-epithelialization and granulation tissue formation, and induced a decrease of arteriole number. In conclusion, we here report that C/EBP gamma positively regulates wound repair both in vitro and in vivo, at least in part, by affecting EGFR signaling. Journal of Investigative Dermatology (2012) 132, 1908-1917; doi:10.1038/jid.2012.51 published online 22 March 2012