We previously showed that the ribonuclease Regnase-1 (Reg1) in keratinocytes plays
a role in mitigating skin inflammation by downregulating proinflammatory cytokines.
In this study, we explored whether Reg1 also has a protective role against skin carcinogenesis.
The chemically induced two-stage carcinogenesis protocol revealed that epidermis-specific
Reg1-deficient (Reg1-knockout [Reg1-cKO]) mice developed skin tumors with shorter latency and more multiplicity than
control mice. In addition, repeated UVB irradiation readily provoked solar keratosis-like
lesions in Reg1-cKO mice. Increased levels of cyclooxygenase 2, whose mRNA (Ptgs2) is reportedly a target of Reg1, have been known to be associated with the development
of squamous cell carcinomas. Indeed, Ptgs2 mRNA levels were upregulated in the skin of Reg1-cKO mice after treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate.
The level of prostaglandin E2 was higher in 12-O-tetradecanoylphorbol-13-acetate‒treated
Reg1-cKO mouse skin than in control mice skin. Moreover, in vivo inhibition of cyclooxygenase
2 attenuated the 12-O-tetradecanoylphorbol-13-acetate‒induced epidermal thickening
in Reg1-cKO mice. Finally, REG1 knockdown in human squamous cell carcinomas lines enhanced PTGS2 mRNA levels after 12-O-tetradecanoylphorbol-13-acetate treatment. In conclusion,
epidermal Reg1 plays a regulatory role not only in skin inflammation but also in tumor
promotion through the downregulation of cyclooxygenase 2. Therefore, forced expression
of Reg1 under inflammatory conditions may be relevant to preventing skin cancer.
Abbreviations:
COX-2 (cyclooxygenase 2), DMBA (7,12-dimethylbenz[a]anthracene), IMQ (imiquimod), KC (keratinocyte), SCC (squamous cell carcinoma), PGE2 (prostaglandin E2), Reg1 (Regnase-1), Reg1-cKO (Regnase-1‒knockout), siRNA (small interfering RNA), TPA (12-O-tetradecanoylphorbol-13-acetate)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: December 02, 2022
Accepted:
November 1,
2022
Received in revised form:
October 7,
2022
Received:
July 14,
2022
accepted manuscript published online XXX; corrected proof published online XXXPublication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
