1. Academic Validation
  2. The Hyperproliferation Mechanism of Cholesteatoma Based on Proteomics: SNCA Promotes Autophagy-Mediated Cell Proliferation through the PI3K/AKT/CyclinD1 Signaling Pathway

The Hyperproliferation Mechanism of Cholesteatoma Based on Proteomics: SNCA Promotes Autophagy-Mediated Cell Proliferation through the PI3K/AKT/CyclinD1 Signaling Pathway

  • Mol Cell Proteomics. 2023 Jul 31;100628. doi: 10.1016/j.mcpro.2023.100628.
Miao Gao 1 Heng Xiao 1 Yonglan Liang 1 Huimin Cai 1 Xiaojing Guo 1 Jianwei Lin 1 Suling Zhuang 1 Jianhua Xu 2 Shengnan Ye 3
Affiliations

Affiliations

  • 1 Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
  • 2 Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122, China. Electronic address: xjh@fjmu.edu.cn.
  • 3 Department of Otorhinolaryngology Head and Neck Surgery, Fujian Institute of Otorhinolaryngology, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Department of Otorhinolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China. Electronic address: yeshengnan63@fjmu.edu.cn.
Abstract

Cholesteatoma is a chronic inflammatory ear disease with abnormal keratinized epithelium proliferation and tissue damage. However, the mechanism of keratinized epithelium hyperproliferation in cholesteatoma remains unknown. Hence, our study sought to shed LIGHT on mechanisms affecting the pathology and development of cholesteatoma, which could help develop adjunctive treatments. To investigate molecular changes in cholesteatoma pathogenesis, we analyzed clinical cholesteatoma specimens and paired ear canal skin with MS-based proteomics and bioinformatics. From our screen, alpha-synuclein (SNCA) was overexpressed in middle ear cholesteatoma (MEC) and might be a key hub protein associated with inflammation, proliferation, and Autophagy in cholesteatoma. SNCA was more sensitive to lipopolysaccharide (LPS)-induced inflammation, and Autophagy marker increase was accompanied by Autophagy activation in middle ear cholesteatoma tissues. Overexpression of SNCA activated Autophagy and promoted cell proliferation and migration, especially under LPS inflammatory stimulation. Moreover, inhibiting Autophagy impaired SNCA-mediated keratinocyte proliferation and corresponded with inhibition of the PI3K/Akt/CyclinD1 pathways. Also, 740Y-P, a PI3K Activator reversed the suppression of Autophagy and PI3K signaling by siATG5 in SNCA overexpressing cells, which restored proliferative activity. Besides, knockdown of SNCA in RHEK-1 and HaCaT cells or knockdown of PI3K in RHEK-1 and HaCaT cells overexpressing SNCA both resulted in attenuated cell proliferation. Our studies indicated that SNCA overexpression in cholesteatoma might maintain the proliferative ability of cholesteatoma keratinocytes by promoting Autophagy under inflammatory conditions. This suggests that dual inhibition of SNCA and Autophagy may be a promising new target for treating cholesteatoma.

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