2. Academic Validation
  3. CD9 downregulation activates EGFR/ERK/WAVE2 pathway to remodel F-actin and promote proliferation and migration of cholesteatoma epithelial cells

CD9 downregulation activates EGFR/ERK/WAVE2 pathway to remodel F-actin and promote proliferation and migration of cholesteatoma epithelial cells

  • Int Immunopharmacol. 2025 Aug 25:164:115401. doi: 10.1016/j.intimp.2025.115401.
Suling Zhuang 1,  Miao Gao 1,  Yonglan Liang 1,  Xiaojing Guo 1,  Qianfeng Li 1,  Jianwei Lin 1,  Jianhua Xu 2,  Shengnan Ye 3
Affiliations

Affiliations

  • 1 Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.; Department of Otolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of The First Afiliated Hospital, Fujian Medical University, Fuzhou 350212, China.; Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.; Fujian Clinical Research Center for Difficult Otorhinolaryngologic Diseases, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
  • 2 The School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350122, Fujian, China.. Electronic address: xjh@fjmu.edu.cn.
  • 3 Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.; Department of Otolaryngology Head and Neck Surgery, National Regional Medical Center, Binhai Campus of The First Afiliated Hospital, Fujian Medical University, Fuzhou 350212, China.; Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.; Fujian Clinical Research Center for Difficult Otorhinolaryngologic Diseases, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.. Electronic address: yeshengnan63@fjmu.edu.cn.
PMID: 40858050 DOI: 10.1016/j.intimp.2025.115401
Abstract

Although overproliferation and high migration of keratinocytes are the key pathological features of middle ear cholesteatoma (MEC), the underlying mechanism remains unclear. We found low CD9 and high ADAM17 expression in MEC specimens, alone with their colocalization, and elevated EGF levels. To investigate the role of CD9 in MEC, we created stable CD9-knockdown keratinocyte cell lines. Results showed enhanced proliferation and migration in CD9-knockdown cells, which were inhibited upon restoring CD9. Exogenous EGF reversed the inhibition. Increased ADAM17 sheddase activity in CD9-knockdown cells promoted the release of EGF, activating the EGFR/ERK/WAVE2 pathway. The colocalization of p-ERK and WAVE2 activated the Arp2/3 complex, promoting F-actin polymerization and pseudopodia formation. Similar findings were observed in MEC specimens. Overall, we confirmed that the reduction of CD9 promotes the proliferation and migration of MEC keratinocytes through F-actin remodeling. Therefore, EGFR or Arp2/3 inhibitors could have therapeutic potential in MEC.

Keywords

CD9; F-actin; Middle ear cholesteatoma; Migration; Proliferation.

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