Survivin promoter -31G/C polymorphism in oral cancer cell lines

Abstract

Abstract. Survivin (SVV) is a protein that belongs to the inhibitor of apoptosis proteins (IAP) family and is involved in the G2/M phase progression of the cell cycle as a spindle-associated molecule. The biological features of this protein are well documented and its activity appears to be involved in mitochondria-dependent and -independent antiapoptotic pathways. Overexpression of SVV at the transcriptional and translational level has been associated with cancer, a multifactorial disorder in which the occurrence of a -31G to C polymorphism in the promoter region may significantly contribute to the development of this pathology. To verify this hypothesis, the occurrence of a single nucleotide polymorphism (SNP) in cis-acting cell cycle-dependent elements (CDEs) and in cell cycle homology regions (CHRs) of the survivin TATA-less promoter was investigated. A total of 23 oral squamous cell carcinoma (OSCC) cell lines and normal epithelium-derived normal human epidermal keratinocyte (NHEK) cell lines were analyzed by RFLP and direct DNA sequencing of their promoter region. Furthermore, survivin expression at the transcriptional and translational levels was evaluated in these cells by RT-PCR and Western blotting, respectively. The findings indicate that the presence of a G or C allele is not directly correlated to survivin expression, at the mRNA or at the protein level, at least in the OSCC lines analyzed in this study. IntroductionSurvivin was discovered by Altieri's group in 1997 (1). The gene coding for survivin was also identified by the same group during a search for the unknown receptor (effector cell protease receptor, epr-1) of blood coagulation factor Xa (2).Survivin is an essential protein that acts as a passenger protein involved in cell division, and belongs to the inhibitor of apoptosis proteins (IAP) family (1-3). Its antiapoptotic zinc-binding domain, baculoviral IAP repeat (BIR), was identified for the first time in a baculoviral protein (4). The human locus is indicated as BIR-containing 5 (BIRC5) and lies on the long arm of chromosome 17 in the telomeric region 25 (17q25) (5). This locus is the source of numerous variant transcripts (survivin, survivin-1α, survivin-2α, survivin-2β, 3β and Δ3), where survivin is the most abundantly transcribed and translated variant in a 142 amino acid-long polypeptide, whereas the minor variants are poorly expressed and investigated (6-9). Furthermore, the occurrence of a natural survivin antisense strand, defined as a distinct gene, codifying for a hypothetical receptor of Xa coagulation factor, epr-1, is well documented (2-10). All of the splicing isoforms share a common promoter belonging to the housekeeping family promoter that is known to be TATA-less and CpG-rich (11).The survivin promoter region was investigated and the minimal promoter region, detected within the proximal -220 nt of the human survivin gene, was found to contain numerous Sp1 sites, three cell cycle-dependent elements (CDEs) and one cell cycle homology region (CHR) implicated in G1 transcrip...

The prognostic significance of survivin expression in patients with HNSCC: a systematic review and meta-analysis

“…The survivin gene locus encodes for multiple alternative splice variants with several different functions and heterodimerization possibilities [ 51 ]. Twenty three HNSCC cell lines at different differentiation levels showed higher survivin expressed levels compared to a human cell line of epidermal keratinocyte [ 52 ]. Targeted therapies have produced striking benefits for patients with cancers.…”

Oral epithelial stem cells—Implications in normal development and cancer metastasis

“…More recently, we reported sialyl Lewis X as a marker that associates with the metastatic abilities of CSC in OSCC [95]. We are currently investigating other putative markers to better characterize oral epithelial stem cells and their metastatic abilities in OSCC, particularly markers that we previously found associated with tumor progression and dissemination in OSCC: Aurora B [118], Survivin [119], beta-catenin [120] that are expressed in the basal layer and invasive front (Figs. 1–2).…”

The -31 G/C promoter gene polymorphism of surviving in Turkish colorectal cancers patients

“…Consistent with the previous studies indicating an elevated frequency for the -31C allele in patients with lung and gastric cancer, our results demonstrated that the -31CC genotype and -31C allele are associated with a significantly increased risk for colorectal cancers. Despite the existing evidence regarding the survivin promoter polymorphism -31G/C and cancer susceptibility, the -31G/C polymorphism has also been investigated in human epidemiological studies to determine whether there was any possible association between this polymorphism and development of cancer [3,[8][9][10][11][12]14].…”

“…Furthermore, studies have suggested the -31 G/C polymorphism of the promoter CDE/CHR repressor element region as a risk factor for the development of gastric cancer and lung cancer [12][13][14][15][16]. In light of available data, our aim in the present study is to investigate the changes in the -31 G/C polymorphism at the CDE/CHR repressor element region in human colorectal cancers.…”