Tang Lipeng, Zhang Bowen, Li Guanzhuo, Qiu Xinmin, Dai Zixin, Liu Hongying, Zhu Ying, Feng Bing, Su Zuqing, Han Wenhui, Huang Huilin, Li Qiuping, Zhang Zihao, Wang Maojie, Liu Huazhen, Chen Yuchao, Zhang Yanmei, Wu Dinghong, Zheng Xirun, Liu Taohua, Zhao Jie, Li Chutian, Zheng Guangjuan
State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
Ann Dermatol. 2024 Oct;36(5):282-291. doi: 10.5021/ad.23.118.
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.
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.
We analyzed microarray data (GSE41662) to investigate the gene expression of in 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 .
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 .
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.
角质形成细胞过度生长是银屑病病因中的关键事件。然而，银屑病角质形成细胞过度增殖的潜在分子机制仍不清楚。
本研究旨在明确S期激酶相关蛋白2（SKP2）在促进银屑病角质形成细胞过度增殖中的潜在作用。
我们分析了基因芯片数据（GSE41662），以研究银屑病皮损皮肤与其相邻非皮损皮肤中基因的表达情况。然后，我们通过实时定量聚合酶链反应和蛋白质免疫印迹法（WB）进一步证实了SKP2在人银屑病皮肤组织、咪喹莫特（IMQ）诱导的银屑病小鼠背部皮肤以及肿瘤坏死因子α（TNF-α）、白细胞介素（IL）-17A和IL-6刺激的角质形成细胞中的mRNA和蛋白质表达。此外，我们通过噻唑蓝（MTT）比色法、细胞周期检测、5-乙炔基-2'-脱氧尿苷染色和WB探索了SKP2在促进角质形成细胞过度增殖中的潜在致病作用及其潜在细胞机制。最后，我们确定抑制SKP2是否能有效缓解角质形成细胞过度增殖。
我们发现SKP2在银屑病皮损皮肤和细胞因子刺激的角质形成细胞中异常上调。此外，上调的SKP2增强了细胞因子诱导的角质形成细胞过度增殖。机制上，增强的SKP2通过抑制细胞周期蛋白依赖性激酶抑制剂p27（P27 Kip1）的表达增加了S期比例。相应地，用SMIP004抑制SKP2可显著减轻表皮增生。
我们的结果表明，升高的SKP2可通过下调P27 Kip1促进角质形成细胞增殖和银屑病样表皮增生。因此，靶向SKP2-P27 Kip1轴可能是未来治疗银屑病的一种有前景的治疗策略。
