Abstract
BackgroundBrain-expressed X-linked (BEX) 4 is a member of BEX family. The functional role of BEX4 in oral squamous cell carcinoma (OSCC) remains unknown.MethodsExpression level of BEX family members (BEX1-5) in OSCC tissues and the paired normal epithelial were examined. Functions of epigenetic changes (DNA methylation and histone modifications) on BEX4 suppression in OSCC were examined by zebularine and trichostatin A (TSA) treatment on OSCC cell lines. Lentivector containing full-length BEX4 was used to generate OSCC cell lines with stable BEX4 expression. Effects of BEX4 expression on OSCC proliferation were monitored with xCELLigence RTCA real-time cell analyzer. BEX4-overexpressing CAL27 was implanted into nude mice to evaluate the effects on tumor growth in vivo. The signaling pathways regulated by BEX4 in OSCC was explored using human whole-transcript expression microarray.ResultsAmong the 5 BEX family members, BEX1 and BEX4 showed significant down-regulation in OSCC (P < 0.001). BEX3, in comparison, was overexpressed in the primary tumor. BEX4 expression in OSCC cell lines was re-activated after zebularine and TSA treatment. High BEX4 expression could suppress proliferation of OSCC in vitro. Subcutaneous tumor volume of BEX4-overexpressing CAL27 was remarkably reduced in nude mice. Microarray experiment showed that S100A family members (S100A7, S100A7A, S100A8, S100A9 & S100A12) might be the downstream targets of BEX4 in OSCC.ConclusionsBEX4 functions as tumor suppressor by inhibiting proliferation and growth of oral cancer. Decreased BEX4 contributes to the increased proliferative propensity of OSCC.
Highlights
Brain-expressed X-linked (BEX) 4 is a member of BEX family
Aberrant expression of BEX4 in oral cancers To identify the key BEX family members involved in oral squamous cell carcinoma (OSCC), we used quantitative polymerase chain reaction (qPCR) to quantify BEX1-5 transcript levels in 65 primary OSCC tissues and compared with the paired normal epithelia
Low BEX4 expression was associated with poor outcome in patients with oral pre-neoplastic lesions We analyzed the association between BEX family member expression and the outcome of 86 oral leukoplakia patients from GSE26549 using SurvExpress
Summary
The functional role of BEX4 in oral squamous cell carcinoma (OSCC) remains unknown. Oral squamous cell carcinoma (OSCC) is the major subtype contributing to over 90 % of the cases [2]. Despite the advances in cancer detection techniques and treatment methods in the past decade, the incidence of OSCC remains high and the 5-year survival rate of OSCC patients remains unsatisfactory [3]. OSCC is an aggressive head and neck cancer due to the rapid proliferative capability and high invasive nature [4]. The survival rate of OSCC patients showed close association with the tumor size [5]. It has been shown that tumor size is an independent predictive factor for survival of OSCC patients [6]. A better understanding on the underlying mechanisms involve in OSCC growth is important to improve the prognosis of OSCC patients
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