The relationship between chronic inflammation and carcinogenesis has been controversial, despite known clinical evidence such as development of squamous cell carcinoma (SCC) from chronic skin ulcer. We previously demonstrated that a ribonuclease Regnase-1 (Reg1) in keratinocytes, played a down-modulator of skin inflammation in a cross-regulatory fashion with proinflammatory signals. Here, we addressed whether Reg1 had a protective role in skin carcinogenesis. The two-stage carcinogenesis protocol allowed keratinocyte-specific Reg1 KO mice (K5.Cre+Reg1fl/fl: Reg1-cKO) mice developed 10 or more papillomas and several SCCs per head, while almost no tumor emerged in controls (Reg1fl/fl). By repeated exposure to ultraviolet B irradiation, Reg1-cKO mice showed marked acanthosis and atypical epidermis resembling solar keratosis at much earlier timing compared with controls. These data indicated that keratinocyte Reg1 had protective roles from tumorigenesis. Among Reg1 target genes, a gene encoding cyclooxygenase-2 (COX-2) Ptgs2 would be a candidate involving cancer prone Reg1-cKO mice since COX-2 contributes to SCC development. As expected, Ptgs2 mRNA expression and PGE2 levels were upregulated in the skin of Reg1-cKO mice treated with TPA. Moreover, COX-2 inhibition attenuated TPA-induced epidermal thickening in Reg1-cKO mice. Finally, we investigated whether Reg1 expression was involved in carcinogenesis in human keratinocytes. Reg1 knock-down in A431 human SCC line resulted in PTGS2 mRNA upregulation with TPA stimulation. In conclusion, our data suggested that epidermal Reg1 played a regulatory role not only in skin inflammation but carcinogenesis through down-modulation of COX-2. Therefore, forced Reg1 expression under the inflammatory condition may be relevant for the prevention of skin cancer.

ESDR436 - Keratinocyte Regnase-1, a down-modulator of skin inflammation, contributes to protection from carcinogenesis through regulating COX-2

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.