LncRNA SOX2OT 调控Nrf2/HO-1信号通路在白癜风发病中的机制研究

Vitiligo is a common depigmented disorder characterized by loss of functional melanocytes and melanin from epidermis. It is difficult to be treated and disfiguration. Oxidative stress as the initiating factor in the pathogenesis of vitiligo, can lead to autoimmune response that targets melanocytes, driving progressive skin depigmentation. As we know,Nrf2/HO-1 signaling pathway is a crucial role in the ability of melanocytes to cope with H2O2-induced oxidative stress in vitiligo.We previously reported that low concentration of H2O2 can upregulate PAR-2 gene expression in a human keratinocyte–melanocyte co-culture system. According to the previous reports, PAR-2 activation enhanced nuclear Nrf2 translocation, and PAR-2-mediated Nrf2 activation was attributable to existing Nrf2 stabilization. Some study suggest that SOX2OT can regulate Nrf2/HO-1 signaling pathway. SOX2 overlapping transcript (SOX2OT) is a long non-coding RNA which harbors one of the major regulators of pluripotency, SOX2 gene, in its intronic region. In recent years , lncRNA has been found to play an important role in epidermal homeostasis, but little is known about the roles of lncRNAs in vitiligo. On the basis of the preparatory work, we want to explore the role of LncRNA SOX2OT in the pathogenesis of vitiligo by clarifying the mechanism of Nrf2/HO-1 signaling pathway in a human keratinocyte–melanocyte co-culture system. We hope this study will help us to find a new target for the treatment of vitiligo.

白癜风是皮肤科常见色素脱失性疾病，治疗困难，毁人容貌。氧化应激作为白癜风发病的始动因素，可引起自身免疫反应，进而攻击黑素细胞最终导致皮肤色素脱失。Nrf2/HO-1信号通路是白癜风发病中的重要抗氧化应激信号通路。本课题在前期研究中采用黑素细胞和角质形成细胞共培养模型，发现一定浓度的过氧化氢可以上调PAR-2基因的表达，而PAR-2激活会促进Nrf2入核并维持其稳定性。亦有研究提示SOX2OT基因可调控Nrf2/HO-1信号通路。SOX2OT基因是一种长链非编码RNA，在SOX2基因的转录调控中起积极的作用。近年研究发现LncRNA在维持皮肤的稳态方面发挥重要的作用，但是在白癜风发病中的作用机制有待研究。本课题拟探讨LncRNA SOX2OT基因调控Nrf2/HO-1信号通路在白癜风发病中的作用，以期寻找白癜风治疗的新靶点。

白癜风是皮肤科常见的色素脱失性疾病，影响患者的外貌，治疗困难，发病机制不明。研究发现氧化应激是白癜风发病的启动因素之一，Nrf2-ARE/HO-1信号通路在氧化应激诱导的白癜风发生过程中具有重要作用。SOX2OT ( NCRNA00043) 是一种长链非编码 RNA，研究表明SOX2OT 基因在 SOX2 基因的转录调控中起积极的作用，SOX2OT 基因和 SOX2 基因在干细胞和一些人类癌症中亲密相伴的表达模式显示他们可能共同调节和参与类似的分子途径。本课题研究发现在进展期白癜风患者组织中黑素细胞缺少或者功能下降，但是LncRNA SOX2OT表达反而高于正常人组织，推测可能与其被激活有关，需要进一步证实。在MC:KC共培养体系中，根据CCK8选择过氧化氢的作用浓度，处理24h模拟白癜风的疾病模型检测氧化应激相关蛋白的表达水平，结果显示白癜风模型中氧化应激相关蛋白表达升高， 抗氧化相关蛋白SOD表达降低。正常黑素细胞敲除SOX2OT后，TRP-1、TRP-2、MITF等黑素合成的相关基因及蛋白表达降低，黑色素合成受到抑制，说明SOX2OT参与黑素细胞的合成。KC:MC共培养体系中加入过氧化氢后，细胞氧化应激水平升高，Nrf2，HO-1及SOD基因被激活；而在同一体系中，SOX2OT敲除后，细胞中Nrf2，HO-1及SOD基因表达及蛋白明显受到抑制，因此推测 SOX2OT可能通过调控Nrf2-ARE/HO-1 信号通路参与氧化应激反应，影响白癜风发病进程。