Upregulated SKP2 Empowers Epidermal Proliferation Through Downregulation of P27 Kip1
10.5021/ad.23.118
- Author:
Lipeng TANG
;
Bowen ZHANG
;
Guanzhuo LI
;
Xinmin QIU
;
Zixin DAI
;
Hongying LIU
;
Ying ZHU
;
Bing FENG
;
Zuqing SU
;
Wenhui HAN
;
Huilin HUANG
;
Qiuping LI
;
Zihao ZHANG
;
Maojie WANG
;
Huazhen LIU
;
Yuchao CHEN
;
Yanmei ZHANG
;
Dinghong WU
;
Xirun ZHENG
;
Taohua LIU
;
Jie ZHAO
;
Chutian LI
;
Guangjuan ZHENG
- Publication Type:Original Article
- From:Annals of Dermatology
2024;36(5):282-291
- CountryRepublic of Korea
- Language:English
-
Abstract:
Background:Excessive growth of keratinocytes is the critical event in the etiology of psoriasis.However, the underlying molecular mechanism of psoriatic keratinocyte hyperproliferation is still unclear.
Objective:This study aimed to figure out the potential contributory role of S-phase kinase-associated protein 2 (SKP2) in promoting the hyperproliferation of keratinocytes in psoriasis.
Methods:We analyzed microarray data (GSE41662) to investigate the gene expression of SKP2in psoriatic lesion skins compared with their adjacent non-lesional skin. Then, we further confirmed the mRNA and protein expression of SKP2 in human psoriatic skin tissues, imiquimod (IMQ)-induced psoriatic mice back skins and tumor necrosis factor α (TNF-α), interleukin (IL)-17A and IL-6-stimulated keratinocytes by using real-time quantitative polymerase chain reaction and western blot (WB). Furthermore, we explored the potential pathogenic role and its underlying cellular mechanism of SKP2 in promoting keratinocytes hyperproliferation through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle detection, 5-ethynyl-2′-deoxyuridine staining and WB. Finally, we determined whether inhibition of SKP2 can effectively alleviate the keratinocytes hyperproliferation in vivo.
Results:We identified that SKP2 is aberrantly upregulated in the psoriatic lesion skin and cytokines-stimulated keratinocytes. Moreover, upregulated SKP2 augments cytokines-induced keratinocytes hyperproliferation. Mechanistically, enhanced SKP2 increased the S phase ratio through inhibiting Cyclin-Dependent Kinase Inhibitor p27 (P27 Kip1) expression. Correspondingly, suppression of SKP2 with SMIP004 can significantly ease the epidermis hyperplasia in vivo.
Conclusion:Our results suggest that elevated SKP2 can empower keratinocytes proliferation and psoriasis-like epidermis hyperplasia via downregulation of P27 Kip1. Therefore, targeting SKP2-P27 Kip1 axis might be a promising therapeutic strategy for the treatment of psoriasis in future.
