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Published on: August 21, 2013
Decreased brain-expressed X-linked 4 (BEX4) expression promotes growth of oral squamous cell carcinoma
Wei Gao1, John Zeng-Hong Li1,2, Si-Qi Chen1
1Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.
Background:
Brain-expressed X-linked (BEX) 4 is a member of BEX family. The functional role of BEX4 in oral squamous cell carcinoma (OSCC) remains unknown.
Methods:
Expression 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.
Results:
Among 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.
Conclusions:
BEX4 functions as tumor suppressor by inhibiting proliferation and growth of oral cancer. Decreased BEX4 contributes to the increased proliferative propensity of OSCC.
Insights
Brain-expressed X-linked 4 (BEX4) acts as a tumor suppressor in oral squamous cell carcinoma (OSCC). Reduced BEX4 levels promote oral cancer cell proliferation and tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Brain-expressed X-linked (BEX) 4 is a member of the BEX gene family.
- The specific role of BEX4 in oral squamous cell carcinoma (OSCC) pathogenesis was previously undefined.
Purpose of the Study:
- To investigate the expression levels of BEX family members in OSCC.
- To elucidate the functional role of BEX4 in OSCC proliferation and tumor growth.
- To identify potential downstream targets and signaling pathways regulated by BEX4 in OSCC.
Main Methods:
- Quantitative analysis of BEX1-5 expression in OSCC tissues and adjacent normal epithelia.
- Epigenetic analysis (DNA methylation, histone modification) of BEX4 regulation using zebularine and trichostatin A (TSA) treatment in OSCC cell lines.
- In vitro proliferation assays using real-time cell analysis (xCELLigence RTCA) and in vivo tumor growth studies in nude mice with BEX4-overexpressing OSCC cells.
- Whole-transcriptome expression microarray analysis to identify BEX4-regulated signaling pathways.
Main Results:
- BEX1 and BEX4 were significantly downregulated in OSCC tissues, while BEX3 was overexpressed.
- BEX4 expression was restored in OSCC cell lines following zebularine and TSA treatment, indicating epigenetic regulation.
- Overexpression of BEX4 suppressed OSCC cell proliferation in vitro and inhibited tumor growth in vivo.
- Microarray analysis suggested S100A family members (S100A7, S100A7A, S100A8, S100A9, S100A12) as potential downstream targets of BEX4.
Conclusions:
- BEX4 functions as a tumor suppressor in oral cancer by inhibiting cell proliferation and tumor growth.
- Downregulation of BEX4 is associated with increased proliferative potential in OSCC, contributing to oral cancer development.
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