Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes
Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes
复制标题
小檗碱通过靶向角质形成细胞中的 JAK-STAT3 信号传导下调 CDC6 并抑制增殖
DOI：
10.1038/s41419-019-1510-8
复制
发表时间：
2019-03-20
影响因子：
9
通讯作者：
Zou, Yongxin
中科院分区：
文献类型：
--
作者：
Sun, Shuna;Zhang, Xiaojie;Zou, Yongxin
银屑病是一种慢性皮肤病，其特征在于表皮角质形成细胞的过度增殖和分化受损，伴有炎症增加，这表明具有抗增殖和抗炎能力的分子可能对其治疗有效。调控细胞增殖的关键步骤之一是DNA复制起始，其依赖于染色质上的复制前复合物（pre-RC）组装。CDC 6是真核细胞中前RC组装和DNA复制的重要调节因子，但其在角质形成细胞和银屑病增殖中的作用尚不清楚。在这里，我们研究了CDC 6在银屑病皮肤中的表达，并评估其在人角质形成细胞增殖中的功能。CDC 6在银屑病皮损表皮细胞中表达上调，并且其可由角质形成细胞中的IL-22/STAT 3信号传导（参与银屑病发病机制的关键信号传导途径）诱导。CDC 6的消耗导致角质形成细胞的增殖减少。我们还发现，小檗碱（BBR）可以抑制角质形成细胞中的CDK 4/6-RB-CDC 6信号转导，导致角质形成细胞增殖减少。BBR的抗增殖作用机制是通过抑制JAK 1、JAK 2和TYK 2，进而抑制STAT 3的活化。最后，我们证明了BBR可以抑制咪喹莫特诱导的小鼠银屑病样皮肤病变和CDC 6和p-STAT 3的上调。总的来说，我们的研究结果表明，BBR通过干扰JAK-STAT 3信号通路抑制人角质形成细胞中的CDC 6表达和增殖。因此，BBR可作为银屑病患者的潜在治疗选择。
Psoriasis is a chronic skin disease characterized by hyperproliferation and impaired differentiation of epidermal keratinocytes accompanied by increased inflammation, suggesting that molecules with antiproliferation and anti-inflammatory abilities may be effective for its treatment. One of the key steps in regulating cell proliferation is DNA replication initiation, which relies on prereplication complex (pre-RC) assembly on chromatin. CDC6 is an essential regulator of pre-RC assembly and DNA replication in eukaryotic cells, but its role in proliferation of keratinocytes and psoriasis is unknown. Here we examined CDC6 expression in psoriatic skin and evaluated its function in the proliferation of human keratinocytes. CDC6 expression is upregulated in epidermal cells in psoriatic lesions and it could be induced by IL-22/STAT3 signaling, a key signaling pathway involved in the pathogenesis of psoriasis, in keratinocytes. Depletion of CDC6 leads to decreased proliferation of keratinocytes. We also revealed that berberine (BBR) could inhibit CDK4/6-RB-CDC6 signaling in keratinocytes, leading to reduced proliferation of keratinocytes. The mechanism of antiproliferation effects of BBR is through the repression of JAK1, JAK2, and TYK2, which in turn inhibits activation of STAT3. Finally, we demonstrated that BBR could inhibit imiquimod-induced psoriasis-like skin lesions and upregulation of CDC6 and p-STAT3 in mice. Collectively, our findings indicate that BBR inhibits CDC6 expression and proliferation in human keratinocytes by interfering the JAK-STAT3 signaling pathway. Thus, BBR may serve as a potential therapeutic option for patients with psoriasis.