Overexpression of DEC1 in the epithelium of OSF promotes mesenchymal transition via activating FAK/Akt signal axis

Abstract

Background: Previous studies on oral submucous fibrosis (OSF) mostly focused on the activation of fibroblasts and collagen metabolism, while little involved in the epithelium. As we have reported the role of differentiated embryo-chondrocyte expressed gene 1 (DEC1) in oral cancer and other precancerous lesions, this research aimed to explore its role in the OSF epithelium.Methods: Expression of DEC1 and other proteins were investigated in tissue array constructed with 33 OSF and 14 normal oral mucosa (NOM) tissues. Human oral keratinocytes treated with arecoline and/or hypoxia were used to simulate OSF epithelium and detected for morphological and protein alterations. Inhibition of DEC1 was used to explore its mediating role. Finally, animal models of OSF constructed by locally arecoline injecting in buccal mucosa were used to verify our findings.Results: DEC1 overexpression could be detected in the epithelium of OSF compared with that in NOM followed by phosphorylated FAK and Akt, and DEC1 showed a significant positive correlation with them. Cytology experiment revealed that OSF-like treatment could upregulate DEC1 expression followed by phosphorylated FAK, Akt, but inhibit E-cadherin, while knockdown of DEC1 could suppress the effects. In addition, OSF mice revealed higher expression of DEC1 in the epithelium of buccal mucosa, along with synchronized alterations of phosphorylated FAK and Akt. Conclusion: In the epithelium of OSF, overexpression of DEC1 induced activation of FAK/Akt signal axis, caused mesenchymal transition in epithelial cells, and may promote malignant transformation of OSF. Targeting DEC1 in OSF could be promising a new target for the diagnosis and treatment of this process. K E Y W O R D S arecoline, differentiated embryo-chondrocyte expressed gene 1, focal adhesion kinase, malignant, oral submucous fibrosis 1 | INTRODUCTION Oral submucous fibrosis (OSF) is a chronic mucosal disease that mainly occurs in the buccal and gingival areas of the oral mucosa, and has attracted attention due to causing progressive restriction of Xin Hu and Weiming Wang contributed equally to this study and should be identified as cofirst authors.

A Critical Interpretive Synthesis of the Role of Arecoline in Oral Carcinogenesis: Is the Local Cholinergic Axis a Missing Link in Disease Pathophysiology?

“…These three studies demonstrated the pro-fibrotic property of arecoline in stimulating collagen deposition in the oral mucosa of mice [8,19,49]. TGF-β, the key player in fibrosis, was shown to increase in response to arecoline exposure [12,21,48].…”

“…Growth and invasion were promoted through the arecoline-induced upregulation of the NOTCH1 gene in mouse models [8,12]. EMT was promoted, activating invasion, and resulting in elevated PTK6 expression with E-cadherin (E-cad) suppression [10], which is deleted in esophageal cancer 1 (DEC1) upregulation, leading to focal adhesion kinase/serine/threonine kinase (FAK/AKT) [49], and through the upregulation of keratin 17 (Krt17) [52] in murine models.…”

“…In in vitro experiments, arecoline has been found to promote EMT in oral epithelial cells through DEC1 upregulation activating FAK/AKT downstream [49], the upregulation of proteasome activator complex subunit 3 (PA28γ), and the phosphorylation of MEK-1 [53] and was found to promote the expression of EMT-related genes [27,34]. Arecoline resulted in a dose-and time-dependent increase in zinc finger protein 1 (SNAI1) expression in human oral keratinocytes (HOKs) and OECM-1 [54].…”

“…Arecoline challenge resulted in squamous cell hyperplasia, increased collagen deposition and fibrotic alteration, and also increased cervical lymph node (LN) metastasis in mice [8,18,19,48,49].…”

Emerging Role of Decoy Receptor-2 as a Cancer Risk Predictor in Oral Potentially Malignant Disorders

“…Immunohistochemical DEC1 expression has been previously studied in tumors from different locations and histology [ 22 , 23 , 24 , 28 ], including some reports in OSCC that describe its role and assess the clinical value of DEC1 expression [ 24 , 26 , 27 , 43 ]. Liudi et al [ 44 ] reported a positive correlation between the expression of DEC1 and HIF-1α, and showed that DEC1 expression was upregulated by hypoxia, thereby leading to the increased motility of OSCC cells.…”