Abstract
BackgroundCigarette smoking is the most significant cause of oral cancer progression. Cigarette smoke condensate (CSC) has been shown to induce endoplasmic reticulum (ER) stress. Binding immunoglobulin protein (BiP) being as an ER stress regulator, has been reported to be implicated in malignant behaviors. Therefore, the aim of this study was to investigate the role of the ER stress-responsive protein, BiP, in CSC-induced oral squamous cell carcinoma (OSCC) malignancy.MethodsThe biological role of BiP in CSC-induced tumor progression was investigated in OSCC cells (YD38 and SCC25) and in a tumor xenograft mouse model. The expressions of related genes were investigated using quantitative RT-PCR and Western blot analysis. Cell migration and invasion were assessed using scratch wound healing and Transwell invasion assays. The effects of conditioned media from OSCC cells on the angiogenic activities of endothelial cells were analyzed using a tube formation assay. The interaction between miR-30a and BiP mRNA was detected using a luciferase reporter assay.ResultsOur results demonstrated that CSC increased the expression of BiP in time- and dose-dependent manners in YD38 and SCC25 cells, and that silencing BiP abrogated CSC-induced cell invasion and tumor-associated angiogenesis. Notably, the putative miR-30a binding site was observed in the 3′untranslated region (UTR) of BiP mRNA, and miR-30a suppressed BiP expression by targeting 3′UTR of BiP transcript. In addition, CSC increased the expression of BiP in OSCC cells by downregulating miR-30a. We also showed that BiP promoted invasion and tumor-associated angiogenesis by increasing the production and secretion of vascular endothelial growth factor in CSC-exposed OSCC cells. Moreover, BiP inhibition suppressed OSCC growth and reduced tumor vessel density in tumor-bearing mice administered with CSC.ConclusionsThese observations suggest that epigenetic regulation of BiP via miR-30a downregulation is involved in CSC-induced OSCC progression.
Highlights
Cigarette smoking is the most significant cause of oral cancer progression
Cigarette smoke conden‐ sate (CSC) induced the expression of Binding immunoglobulin protein (BiP) in oral squamous cell carcinoma (OSCC) cells in time‐ and dose‐dependent manners Cigarette smoking is a significant risk factor for oral cancer development and progression, and it has been demonstrated to trigger endoplasmic reticulum (ER) stress-associated responses [11, 44]
Dose- and CSC stimulated Epithelial–mesenchymal transition (EMT) change, migration, invasion and tumor‐associated angiogenesis in OSCC cells Previous studies have reported that BiP is involved in the regulation of tumor function, including epithelial–mesenchymal transition (EMT) change, migration, invasion, and tumor-associated angiogenesis, and that vascular endothelial growth factor (VEGF) is a downstream regulator of BiP participating in these pathological processes [45,46,47]
Summary
Cigarette smoking is the most significant cause of oral cancer progression. The aim of this study was to investigate the role of the ER stress-responsive protein, BiP, in CSC-induced oral squamous cell carcinoma (OSCC) malignancy. Cigarette smoking has been shown to contribute to the cancer-associated transformation of oral epithelial cells [14]. Cigarette smoke condensate (CSC) treatment has been reported to increase the invasion and migration of OSCC cells [15]. These findings suggest the role of cigarette smoking in the carcinogenesis and disease progression of oral cancer. Little is known about the role of epigenetic alterations in CSC-induced oral cancer progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
