Abstract
BackgroundEpithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor for Rho family GTPase, which has been implicated in the malignant phenotype of human cancers. Little is known about the effect of a high level of ECT2 in regulating oral cancer cell behavior. In this study, we investigated the involvement of ECT2 in oral squamous cell carcinoma (OSCC).Methodology/Principal FindingsWe analyzed ECT2 expression in OSCC-derived cell lines and primary OSCCs compared with matched normal tissue (n = 96) by quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. We then evaluated the correlation between the ECT2 expression status in primary OSCCs and the clinicopathological features. ECT2 expression was significantly up-regulated in OSCCs in vitro and in vivo (p<0.05). Among the clinical variables analyzed, higher ECT2 expression also was associated with the TNM stage grading (p<0.05). When we performed functional analyses of ECT2 in OSCC-derived cells using the shRNA system, the cellular proliferation of the ECT2 knockdown cells decreased significantly compared with the control cells (p<0.05). Cell cycle analysis by flow cytometry showed arrest of cell cycle progression at the G1 phase in the ECT2 knockdown cells. We also found up-regulation of the Cip/Kip family of the cyclin-dependent kinase inhibitors, p21cip1 and p27kip1, and down-regulation of cyclin D1, cyclin E, and CDK4. These data suggested that the elevated Cip/Kip family induced inhibition of the cyclin D1-CDK complex activity leading to cell cycle arrest at the G1 phase.Conclusions/SignificanceOur results proposed for the first time that ECT2 is an indicator of cellular proliferation in OSCCs and that ECT2 might be a potential therapeutic target for the development of new treatments for OSCCs.
Highlights
Oral squamous cell carcinoma (OSCC) is a major cause of morbidity and mortality globally, accounting for 275,000 new cases and more than 120,000 deaths annually [1]
To investigate mRNA expression of Epithelial cell transforming sequence 2 (ECT2) identified as a cancer-related gene by our microarray analysis [6], we performed quantitative reverse transcriptase PCR analysis using six oral squamous cell carcinoma (OSCC)-derived cell lines (HSC-2, HSC-3, HSC-4, H1, Ca9-22, and Sa3) and human normal oral keratinocytes (HNOKs). mRNA expression levels were normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
ECT2 mRNA was significantly up-regulated in all OSCC cell lines compared with the HNOKs (Figure 1A, *p,0.05)
Summary
Oral squamous cell carcinoma (OSCC) is a major cause of morbidity and mortality globally, accounting for 275,000 new cases and more than 120,000 deaths annually [1]. Molecular changes in a number of oncogenes and tumor suppressor genes associated with the development of OSCC could be important clues to preventing this disease [4,5]. Epithelial cell transforming sequence 2 (ECT2) was significantly up-regulated in OSCC. ECT2 is a guanine nucleotide exchange factor (GEF) for Rho family GTPase related to cytokinesis [7,8,9,10,11]. The Rho GTPases have been implicated in the malignant phenotype of human cancers as a result of their participation in aberrant signaling in tumor cells [12,13,14,15,16,17]. Epithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor for Rho family GTPase, which has been implicated in the malignant phenotype of human cancers. We investigated the involvement of ECT2 in oral squamous cell carcinoma (OSCC)
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