Abstract
Cell division cycle associated 2 (CDCA2) recruits protein phosphatase 1 to chromatin to antagonize activation of ataxia telangiectasia mutated (ATM)-dependent signal transduction. ATM kinase plays a critical role in the DNA damage response and its phosphorylation cascade to inhibit the p53-MDM2 interaction, which releases p53 to induce p21 and G1 cell-cycle arrest. However, the relevance of CDCA2 to human malignancy including oral squamous cell carcinoma (OSCC) is unknown. In the current study, we found that CDCA2 expression was up-regulated in OSCC cell lines. Functional studies with shRNA system showed that knockdown of CDCA2 significantly (P<0.05) inhibited cellular proliferation compared with the control cells by arresting cell-cycle progression at the G1 phase and up-regulating the cyclin-dependent kinase inhibitors (p21Cip1, p27Kip1, p15INK4B, and p16INK4A). CDCA2 knockdown also promoted apoptosis after treatment with the DNA damage reagent, cisplatin. In clinical samples, the CDCA2 protein expression level in primary OSCCs was significantly (P<0.05) greater than in matched normal oral tissues (67/85, 79%). Furthermore, CDCA2-positive cases were correlated significantly (P<0.05) with high cancer progression. Our results showed for the first time that CDCA2 frequently is overexpressed in OSCCs and might be associated closely with OSCC progression by preventing cell-cycle arrest and apoptosis.
Highlights
The main carcinogenic agents associated with tumoral development in the upper aerodigestive tract including the oral cavity are tobacco and alcohol, which damage cells and the genetic code [1,2]
To investigate mRNA and protein expression of Cell division cycle associated 2 (CDCA2) identified as a cancer-related gene in our previous microarray data [8], we performed quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blot analyses using six oral squamous cell carcinoma (OSCC)-derived cell lines (HSC-2, HSC-3, HSC-4, Ca9-22, Ho-1u-1, and Sa3), the HeLa cell line, and the human normal oral keratinocytes (HNOKs)
CDCA2 mRNA was significantly (*P,0.05) up-regulated in all OSCCderived cell lines and the HeLa cell line compared with the HNOKs (Figure 1A)
Summary
The main carcinogenic agents associated with tumoral development in the upper aerodigestive tract including the oral cavity are tobacco and alcohol, which damage cells and the genetic code [1,2]. A defective DNA damage response (DDR) can result in apoptosis or possibly genomic instability, unregulated cell growth, and increased cancer risk [4]. Recent reports have shown that DDR is activated in early precancerous cells as a barrier to suppress cellular proliferation and cancer progression [5]. In addition to a defective DDR, misregulated cyclin-dependent kinases (CDKs), the cell division cycle controller, are related to carcinogenesis by inducing unscheduled proliferation and genomic and chromosomal instability [6]. Understanding the functional consequences of the dysregulation of the cell-cycle apparatus and intranuclear mechanisms that signal apoptosis after DNA damage in oral squamous cell carcinoma (OSCC) will uncover novel diagnostic and therapeutic approaches
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