Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China.
Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
J Invest Dermatol. 2019 Jan;139(1):124-134. doi: 10.1016/j.jid.2018.07.020. Epub 2018 Aug 16.
Nicastrin (NCSTN) mutations are associated with familial acne inversa (AI), and emerging evidence suggests that microRNAs (miRNAs) are involved in various skin diseases. However, whether NCSTN mutations affect miRNA levels and their subsequent signaling pathways in familial AI patients has not been studied. We aimed to elucidate the relationship between NCSTN mutations and familial AI pathogenesis by investigating differential miRNA expression and their related pathways. Combined with miRNA microarray data from familial AI patients, Ncstn keratinocyte-specific-knockout (Ncstn) mice and bioinformatics predictions showed that NCSTN mutations led to decreased miR-30a-3p levels, which negatively regulated RAB31 expression. Moreover, enhanced RAB31 levels accelerated degradation of activated EGFR, leading to abnormal differentiation in keratinocytes. The impaired EGFR signaling and its effects on epidermal differentiation were also observed in familial AI patients and Ncstn mice. Thus, our study showed that miR-30a-3p/RAB31/EGFR signaling pathway may play a key role in the pathogenesis of familial AI with NCSTN mutations.
尼克斯特林（NCSTN）突变与家族性倒痤疮（AI）有关，新出现的证据表明 microRNAs（miRNAs）参与各种皮肤疾病。然而，NCSTN 突变是否影响家族性 AI 患者的 miRNA 水平及其后续信号通路尚未研究。我们旨在通过研究差异表达的 miRNA 及其相关通路，阐明 NCSTN 突变与家族性 AI 发病机制之间的关系。结合家族性 AI 患者的 miRNA 微阵列数据、Ncstn 角质形成细胞特异性敲除（Ncstn）小鼠和生物信息学预测，表明 NCSTN 突变导致 miR-30a-3p 水平降低，负调控 RAB31 表达。此外，增强的 RAB31 水平加速了激活的 EGFR 的降解，导致角质形成细胞的异常分化。在家族性 AI 患者和 Ncstn 小鼠中也观察到受损的 EGFR 信号及其对表皮分化的影响。因此，我们的研究表明，miR-30a-3p/RAB31/EGFR 信号通路可能在 NCSTN 突变引起的家族性 AI 发病机制中发挥关键作用。
