Date Published: April 18, 2019
Publisher: Public Library of Science
Author(s): Khvaramze Shaverdashvili, Jennie Padlo, Daniel Weinblatt, Yang Jia, Wenpeng Jiang, Divya Rao, Dorottya Laczkó, Kelly A. Whelan, John P. Lynch, Amanda B. Muir, Jonathan P. Katz, Claudia D. Andl.
Understanding the regulatory mechanisms within esophageal epithelia is essential to gain insight into the pathogenesis of esophageal diseases, which are among the leading causes of morbidity and mortality throughout the world. The zinc-finger transcription factor Krüppel-like factor (KLF4) is implicated in a large number of cellular processes, such as proliferation, differentiation, and inflammation in esophageal epithelia. In murine esophageal epithelia, Klf4 overexpression causes chronic inflammation which is mediated by activation of NFκB signaling downstream of KLF4, and this esophageal inflammation produces epithelial hyperplasia and subsequent esophageal squamous cell cancer. Yet, while NFκB activation clearly promotes esophageal inflammation, the mechanisms by which NFκB signaling is activated in esophageal diseases are not well understood. Here, we demonstrate that the Rho-related GTP-binding protein RHOF is activated by KLF4 in esophageal keratinocytes, leading to the induction of NFκB signaling. Moreover, RHOF is required for NFκB activation by KLF4 in esophageal keratinocytes and is also important for esophageal keratinocyte proliferation and migration. Finally, we find that RHOF is upregulated in eosinophilic esophagitis, an important esophageal inflammatory disease in humans. Thus, RHOF activation of NFκB in esophageal keratinocytes provides a potentially important and clinically-relevant mechanism for esophageal inflammation and inflammation-mediated esophageal squamous cell cancer.
Esophageal diseases are among the leading causes of morbidity and mortality in the U.S. and the world . For example, esophageal cancers, of which approximately 90% are esophageal squamous cell cancer (ESCC) , are the 8th most common cause of cancer and the 6th leading cause of cancer-related deaths worldwide [3, 4]. Many diseases of the squamous esophagus, including ESCC and eosinophilic esophagitis (EoE), occur in the setting of chronic inflammation, and a number of these conditions have been effectively modeled in the mouse, leading to new insights into molecular pathogenesis of these diseases [5–10]. In particular, the NFκB signaling pathway has emerged as a critical activator of epithelial inflammation and inflammation-mediated carcinogenesis [11, 12], and in the esophagus, activated NFκB signaling is implicated in the development of ESCC and EoE, among other disorders [7, 13–20]. Moreover, constitutive NFκB activation in murine esophagus promotes inflammation and angiogenesis in vivo . However, to date, the molecular mechanisms governing NFκB pathway activation in esophageal epithelia are not well understood.
In the esophagus, activation of proinflammatory pathways within esophageal squamous epithelial cells can promote inflammation throughout the mucosa, providing a microenvironment favorable for the development of ESCC [5–8]. Previously, we demonstrated that transgenic overexpression of Klf4 within esophageal keratinocytes activates NFκB signaling, which is associated with the development numerous inflammatory diseases and cancers [11–20], resulting in inflammation-mediated ESCC . We also showed that, consistent with this, activation of NFκB signaling within esophageal keratinocytes by transgenic Ikkβ expression promotes inflammation and angiogenesis, features of inflammatory diseases and the tumor microenvironment [5, 63, 64]. The Rho GTPases interact with the NFκB pathway and are involved in the pathogenesis of a number of human cancers and other inflammatory diseases . Here, we link the Rho family member RHOF to KLF4-mediated NFκB activation in esophageal keratinocytes and to the development of inflammation and a human esophageal inflammatory disease, EoE.