The circEPSTI1/mir-942-5p/LTBP2 axis regulates the progression of OSCC in the background of OSF via EMT and the PI3K/Akt/mTOR pathway

Jie Wang,Lina Yang,Fei Wang,Caiyun He,Canhua Jiang,Zaiye Li,Ying Xu,Zhengzhong Shen,Ning Li

doi:10.1038/s41419-020-02851-w

Abstract

Oral squamous cell carcinoma (OSCC) in the background of oral submucous fibrosis (OSF) caused by areca nut chewing has a high incidence in Asia-Pacific countries. However, the molecular mechanism remains unclear. Here, we performed circRNA microarray analysis to screen the circRNA expression profiles in OSCC and OSF. We identified circEPSTI1 as a circRNA with consistent, sequential upregulation from normal buccal mucosa (NBM) to OSF to OSCC. Functionally, circEPSTI1 significantly promoted OSCC cell proliferation and invasion, as evidenced by the CCK8, colony formation, wound healing, and transwell assays with circEPSTI1 overexpression and silencing. OSCC patients with circEPSTI1high status exhibited poor prognoses. CircEPSTI1 sponged miR-942-5p and accelerated epithelial-mesenchymal transition (EMT) to increase LTBP2 expression in OSCC through phosphorylation of PI3K/Akt/mTOR signaling pathway components. Blocking the PI3K/Akt/mTOR signaling pathway with the dual PI3k/mTOR inhibitor BEZ235 reversed OSCC progression induced by overexpression of circEPSTI1 and LTBP2. Collectively, these results indicate that the circEPSTI1/miR-942-5p/LTBP2 axis affects OSCC cell proliferation and invasion via the acceleration of EMT and the phosphorylation of PI3K/Akt/mTOR signaling pathway components. CircEPSTI1 may be an independent diagnostic and prognostic marker and a potential therapeutic target for OSCC patients with OSF.

Highlights

Tobacco or alcohol use, betel quid or areca nut chewing, sharp residual roots and crowns of teeth and human papillomavirus are well-established etiologic agents for oral squamous cell carcinoma (OSCC)
CircEPSTI1 expression is consistently upregulated from normal buccal mucosa (NBM) to oral submucous fibrosis (OSF) to OSCC
CircEPSTI1, which is located on chromosome 13q14 and confirmed by Sanger sequencing (Supplemental Fig. Sa), exhibited the most significant upregulation in OSCC tissue compared to OSF and NBM tissue (Fig. 1b)

Summary

Introduction

Betel quid or areca nut chewing, sharp residual roots and crowns of teeth and human papillomavirus are well-established etiologic agents for oral squamous cell carcinoma (OSCC). Among these agents, areca nut, which is commonly chewed in South and Southeast Asian countries and some provinces in China, is a highly unique pathogenic factor. OSCC in the background of OSF is one of the most common malignancies in South and Southeast Asian countries and China because of the increasing popularity of commercial areca nut and the increased uptake by young people[5].

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Results

Conclusion