The association between the survivin −31G/C promoter polymorphism and hepatocellular carcinoma risk in a Turkish population
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the worldwide and the third leading cause of cancer death. Because of its high fatality rates, the incidence and mortality rates are approximately equal [1]. It is now well established that multiple risk factors contribute to hepatocarcinogenesis, including chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, cirrhosis, carcinogen exposure (such as aflatoxin B1), excessive alcohol drinking, and a number of genetic and epigenetic alterations [2], [3]. However, HBV and HCV infections are the major cause of HCC, only a fraction of infected patients develop HCC during their lifetime; therefore the identification of other risk characteristics (such as genetic polymorphisms) to stratify those individuals into high-risk populations is needed. As in many cancers, genetic polymorphisms involved in multistage of hepatocarcinogenesis may determine individual's susceptibility to the development of HCC [4], [5]. The identification of single nucleotide polymorphisms (SNPs) that affect gene function or expression and contribute to HCC susceptibility is important as it may help to predict individual and population risk and clarify pathophysiologic mechanisms relevant to HCC. Moreover, identifying genetic biomarkers of HCC susceptibility and their application in conjunction with traditional diagnosis, staging and prognosis, it might be possible to reduce HCC mortality through early diagnosis, patients care and personalized therapy [6].
Dysregulations of the balance between proliferation and cell death are involved in carcinogenesis including hepatocarcinogenesis through prolonging cell survival, promoting accumulation of transforming mutations, and enhancing resistance to therapy [7], [8]. Indeed, recent studies have suggested that some molecules involved in counteracting apoptosis, such as Bcl-XL, Mcl-1, c-IAP1, XIAP and survivin are overexpressed in HCC [7], [9]. Survivin, a member of the inhibitor of apoptosis proteins (IAPs) family, is involved in inhibition of apoptosis and regulation of cell division [10]. Survivin's cell division regulatory function is executed by binding several structural components of the mitotic apparatus, i.e. spindle microtubules, centrosomes or kinetochores of metaphasic chromosomes [11]. Survivin, discovered in 1997, is a 16.3 kDa protein consisting of 142 amino acids. The gene encoding survivin is of 14.5 kb, which is located at the telomeric region of the chromosome 17q25 [10]. Previous studies found that survivin was undetectable in terminally differentiated adult tissues. However, growing evidence indicates that survivin is expressed in normal adult cells, and that it plays a role in certain physiological processes in many human cells [12], [13]. One of the most significant features of survivin is its different expression in cancer compared to normal tissues. In various human cancers including hepatocellular cancer, survivin is strongly overexpressed and has been established as a prognostic marker [9]. Increased survivin expression in human cancers is considered to be an important marker for aggressive and chemoresistant disease, signaling a poor prognosis [14]. Morever, Ye et al. [15] have suggested that survivin overexpression is correlated with high risk of disease recurrence and poor prognosis in HCC.
Survivin is expressed in a cell cycle-dependent manner, with maximal expression during G2/M phase of the cell cycle and exhibits a rapid downregulation in G1 phase [11]. This is largely controlled at the transcriptional level, and mediated by several cell cycle-dependent elements (CDEs) (GGCGG) and one cell cycle homology region (CHR) (ATTTGAA) located in the proximal region of the survivin promoter [16]. Several SNPs were identified within the promoter region of the survivin gene, one of which is located at the CDE/CHR repressor binding site (−31 bp from the first nucleotide of the ATG start codon) [17]. The reference number of this SNP in the database of the National Center for Biotechnology Information (NCBI) is rs9904341. The best documented of this SNP is at position −31 of the survivin gene promoter and involves the substitution of guanine (G) for cytosine (C) and the creation of two alleles (−31G and −31C) and three genotypes GG, GC, and CC. Survivin −31G/C polymorphism has been associated with overexpression of survivin at both messenger RNA (mRNA) and protein levels and abberant cell cycle-dependent transcription mediated through functional disruption of binding at the CDE/CHR repressor motifs in a number of cancer cell lines [17].
Several case–control studies have investigated the association between −31G/C polymorphism within the CDE/CHR repressor element of the survivin gene promoter and cancer risk including lung cancer [18], sporadic colorectal cancer [19], cervical cancer [20], gastric cancer [21], esophageal squamous cell carcinoma [22], urothelial carcinoma [23], pancreatic cancer [24] and acute myeloid leukemia [25]. However, conflicting results have been published [18], [19], [20], [21], [22], [23], [24], [25].
Based on the important role of survivin in carcinogenesis, with important biological, prognostic and therapeutic implications. We hypothesized that functional −31G/C polymorphism in survivin gene may act as a genetic modifier in individual susceptibility to HCC. According to our recent knowledge, no research has been conducted to evaluate survivin −31G/C polymorphism and risk of HCC development. To test the hypothesis that the polymorphism of survivin −31G/C is associated with risk of developing HCC, we performed genotyping analysis using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a hospital-based case–control study of 160 HCC patients and 241 age, gender, smoking and alcohol consumption matched cancer-free controls in Turkish population.
Section snippets
Study population
The study population and subject characteristics were previously described elsewhere [4], [5]. This is an ongoing molecular epidemiologic study of HCC conducted in Adana, Turkey and the subjects recruitment was approved by the Committee for Ethics of Medical Experiment on Human Subjects, Faculty of Medicine, Çukurova University. Briefly, all subjects were genetically unrelated Turkish and were from Çukurova and the surrounding regions of southern Turkey. Submission of the individuals to the
General characteristic of the subjects
A total of 401 Turkish subjects were enrolled in our study. General characteristic of the subjects are summarized in Table 1. As expected, no significant difference was found between case patients and control subjects with regard to age and sex (p = 0.85 and p = 0.98, respectively) which implied that age and sex matched adequately. Similarly, there were no significant differences in smoking status and alcohol consumption between case and control group. In addition to these, Table 1 shows the
Discussion
It is widely accepted that the regulation of programmed cell death is important for the prevention of tumorigenesis. Impairment of apoptosis facilitates the accumulation of genetic errors by prolonging the cell cycle, promoting resistance to immune-based cytotoxicity, and a selective growth advantage for the altered cells contributing to carcinogenesis [7], [14]. Because survivin functions as an inhibitor of apoptosis that is essential for eliminating mutated or transformed cells from body, it
Conflict of interest
All authors declare that there are no conflicts of interest.
Acknowledgements
The authors thank all the subjects who participated in this study. This work was supported by Çukurova University Research Fund FEF2008D4.
References (36)
- et al.
Hepatocellular carcinoma: epidemiology and molecular carcinogenesis
Gastroenterology
(2007) - et al.
Cyclin D1 G870A polymorphism is associated with an increased risk of hepatocellular carcinoma in the Turkish population: case–control study
Cancer Epidemiol
(2010) - et al.
Structural, functional and therapeutic biology of survivin
Cancer Lett
(2006) - et al.
Role of the Survivin gene in pathophysiology
Am J Pathol
(2006) - et al.
Survivin: a promising tumor biomarker
Cancer Lett
(2007) - et al.
Polymorphisms in the survivin gene and the risk of lung cancer
Lung Cancer
(2008) - et al.
Association between survivin gene promoter −31 C/G polymorphism and urothelial carcinoma risk in Taiwanese population
Urology
(2009) - et al.
Epigenetic and genetic analysis of the survivin promoter in acute myeloid leukemia
Leuk Res
(2008) - et al.
Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver
J Hepatol
(2001) - et al.
DNA demethylase is expressed in ovarian cancers and the expression correlates with demethylation of CpG sites in the promoter region of c-erbB-2 and survivin genes
Cancer Lett
(2001)