Abstract
To evaluate the carcinogenicity of p27 knockout (KO) mice with RNA-guided endonuclease (RGENs)-mediated p27 mutant exon I gene (IΔ), alterations in the carcinogenic phenotypes including tumor spectrum, tumor suppressor proteins, apoptotic proteins and cell cycle regulators were observed in p27 (IΔ) KO mice after treatment with 7,12-Dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA)(DT) for 5 months. The target region (544~571 nt) in exon I of the p27 gene was successfully disrupted in p27 (IΔ) KO mice using the RGEN-induced non-homologous end joining (NHEJ) technique. After DT exposure for 5 months, a few solid tumors (identified as squamous cell carcinoma) developed on the surface of back skin of DT-treated p27 (IΔ) KO mice. Also, squamous cell hyperplasia with chronic inflammation was detected in the skin dermis of DT-treated p27 (IΔ) KO mice, while the Vehicle+p27 (IΔ) KO mice and WT mice maintained their normal histological skin structure. A significant increase was observed in the expression levels of tumor suppressor protein (p53), apoptotic proteins (Bax, Bcl-2 and Caspase-3) and cell-cycle regulator proteins (Cyclin D1, CDK2 and CDK4) in the skin of DT-treated p27 (IΔ) KO mice, although their enhancement ratio was varied. Taken together, the results of the present study suggest that squamous cell carcinoma and hyperplasia of skin tissue can be successfully developed in new p27 (IΔ) KO mice produced by RGEN-induced NHEJ technique following DT exposure for 5 months.
Highlights
P27Kip1 is a well-known member of the Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors [1]
Carcinogenesis of p27 (IΔ) KO mice treated with DT we examined the tumor development in p27 (IΔ)
These results indicate that squamous cell carcinoma and hyperplasia can be successfully induced by DT treatment in RGENmediated p27 (IΔ) KO mice
Summary
P27Kip is a well-known member of the Cip/Kip family of cyclin-dependent kinase (Cdk) inhibitors [1] It suppresses the cell cycle progression from G1 phase to the S phase by binding to the cyclin/Cdk complex, resulting in G1 arrest of the cell cycle [2,3]. The p27 (IΔ) KO mice generated by the RGEN technique have never been considered to investigate the organ sensitivity on chemically induced carcinogenesis. This study investigated the carcinogenicity in RGENS-mediated p27 (IΔ) KO mice after exposure to DT These results provide novel evidence that squamous cell carcinoma of the skin tissue and alterations of cancer-related proteins in p27 (IΔ) KO mice can be successfully induced by DT treatment for 5 months, other cancers were not observed in the various tissues
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