Identification of a BRAF/PA28γ/MEK1 signaling axis and its role in epithelial-mesenchymal transition in oral submucous fibrosis

Abstract

Oral submucous fibrosis (OSF) is a chronic and insidious oral potentially malignant disorder associated with a 4–17% risk of oral squamous cell carcinoma (OSCC). Our previous study found that proteasomal activator 28 gamma (PA28γ) is frequently overexpressed in oral squamous cell carcinoma and negatively correlated with poor patient prognosis. However, the role of PA28γ in the occurrence and development of OSF remains unclear. Here, we screened PA28γ-related genes and investigated their function in OSF. We demonstrated that the expression of PA28γ was positively associated with MEK1 and gradually elevated from normal to progressive stages of OSF tissue. Arecoline, a pathogenic component of OSF, could upregulate the protein levels of PA28γ and phosphorylated MEK1 and contribute to epithelial to mesenchymal transition (EMT) in epithelial cells. Notably, PA28γ could interact with MEK1 and upregulate its phosphorylation level. Furthermore, arecoline upregulated BRAF, which can interact with PA28γ and upregulate its protein level. Additionally, BRAF, PA28γ, and MEK1 could form protein complexes and then enhance the MEK1/ERK signaling pathways. The concrete mechanism of the protein stability of PA28γ is that BRAF mediates its degradation by inhibiting its ubiquitination. These findings underscore the instrumental role of PA28γ in the BRAF/MEK1 pathway and enhanced EMT through MEK1/ERK activation in OSF.

Exosomal miR-17-5p derived from epithelial cells is involved in aberrant epithelium-fibroblast cross-talk and induces the development of oral submucosal fibrosis

“…32 Our previous study found that arecoline can activate the BRAF/MEK1 signaling pathway in epithelial cells, which ultimately promotes epithelialmesenchymal transition. 33 However, it is not clear how epithelial cells drive the differentiation of broblasts to participate in brosis development.…”

Arecoline promotes Akt‐c‐Myc‐driven aerobic glycolysis in esophageal epithelial cells

“…The primary psychoactive component of areca nuts, arecoline (Are), has been identified as a Group I human carcinogen by the International Agency for Cancer Research, 15,16 and has been shown to significantly increase the risk of oral and ECs 17,18 . Chewing areca nuts can result in the mouth conditions of oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC), both of which have the potential to develop into cancer 19,20 . In OSCC and OSF, 18 arecoline has the ability to cause inflammation and release reactive oxygen species (ROS) 17 .…”

“…17,18 Chewing areca nuts can result in the mouth conditions of oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC), both of which have the potential to develop into cancer. 19,20 In OSCC and OSF, 18 arecoline has the ability to cause inflammation and release reactive oxygen species (ROS). 17 Arecoline's effects on esophageal epithelial cells have not been thoroughly understood, though.…”

Correlations between schizophrenia and lichen planus: a two-sample bidirectional Mendelian randomization study

“…Lesions of LP in the oral mucosa can hinder the patient’s ability to eat, while those on exposed skin can significantly disrupt their social and daily activities. Oral lichen planus, a potentially malignant disorder, has no known cure and carries the risk of progressing into oral squamous cell carcinoma ( 12 , 13 ). Thus, early detection and appropriate management of oral lichen planus are crucial in preventing the development of oral cancer.…”