KLF4 activates NFκB signaling and esophageal epithelial inflammation via the Rho-related GTP-binding protein RHOF

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.解析食管上皮的调控机制，对于深入理解食管疾病的发病机制至关重要——而食管疾病是全球范围内引发高发病率与高死亡率的主要病因之一。锌指转录因子Krüppel样因子（Krüppel-like factor, KLF4）参与调控食管上皮内的诸多细胞生物学过程，包括增殖、分化与炎症反应。在小鼠食管上皮中，Klf4过表达会引发慢性炎症，该炎症过程由KLF4下游的NFκB信号通路激活所介导；而此类食管炎症会导致上皮增生，并进一步诱发食管鳞状细胞癌。然而，尽管NFκB激活可明确促进食管炎症，但食管疾病中NFκB信号通路的激活机制仍未被充分阐明。本研究证实，在食管角质形成细胞中，KLF4可激活Rho家族GTP结合蛋白RHOF，进而诱导NFκB信号通路的活化。此外，在食管角质形成细胞中，RHOF是KLF4介导NFκB激活的必需因子，同时对食管角质形成细胞的增殖与迁移亦发挥关键作用。最后，本研究发现，在人类重要的食管炎症性疾病——嗜酸性食管炎患者的组织中，RHOF表达上调。综上，食管角质形成细胞中RHOF对NFκB的激活通路，为食管炎症以及炎症介导的食管鳞状细胞癌提供了一个具有重要临床意义的潜在机制。