Jin Lin, Kashyap Mahendra P, Chen Yunjia, Khan Jasim, Guo Yuanyuan, Chen Jari Q, Lee Madison B, Weng Zhiping, Oak Allen, Patcha Prasanth, Mayo Tiffany, Sinha Rajesh, Atigadda Venkatram, Mukhtar Shahid M, Deshane Jessy S, Raman Chander, Elston Carly, Elewski Boni E, Elmets Craig A, Athar Mohammad
Center for Epigenomics and Translational Research in Inflammatory Skin Diseases, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
iScience. 2023 May 19;26(6):106896. doi: 10.1016/j.isci.2023.106896. eCollection 2023 Jun 16.
Hidradenitis suppurativa (HS) is a skin disorder that causes chronic painful inflammation and hyperproliferation, often with the comorbidity of invasive keratoacanthoma (KA). Our research, employing high-resolution immunofluorescence and data science approaches together with confirmatory molecular analysis, has identified that the 5'-cap-dependent protein translation regulatory complex eIF4F is a key factor in the development of HS and is responsible for regulating follicular hyperproliferation. Specifically, eIF4F translational targets, Cyclin D1 and c-MYC, orchestrate the development of HS-associated KA. Although eIF4F and -eIF4E are contiguous throughout HS lesions, Cyclin D1 and c-MYC have unique spatial localization and functions. The keratin-filled crater of KA is formed by nuclear c-MYC-induced differentiation of epithelial cells, whereas the co-localization of c-MYC and Cyclin D1 provides oncogenic transformation by activating RAS, PI3K, and ERK pathways. In sum, we have revealed a novel mechanism underlying HS pathogenesis of follicular hyperproliferation and the development of HS-associated invasive KA.
化脓性汗腺炎（HS）是一种导致慢性疼痛性炎症和过度增殖的皮肤疾病，常伴有侵袭性角化棘皮瘤（KA）的合并症。我们的研究采用高分辨率免疫荧光和数据科学方法以及验证性分子分析，已确定5'-帽依赖性蛋白质翻译调控复合物eIF4F是HS发生发展的关键因素，并负责调节毛囊过度增殖。具体而言，eIF4F的翻译靶点细胞周期蛋白D1（Cyclin D1）和c-MYC协调了与HS相关的KA的发生发展。尽管在整个HS病变中eIF4F和-eIF4E相邻，但Cyclin D1和c-MYC具有独特的空间定位和功能。KA充满角蛋白的火山口是由细胞核内c-MYC诱导的上皮细胞分化形成的，而c-MYC和Cyclin D1的共定位通过激活RAS、PI3K和ERK途径提供致癌转化作用。总之，我们揭示了一种HS发病机制中毛囊过度增殖以及与HS相关的侵袭性KA发生发展的新机制。
