Original article
The correlation between XIAP gene polymorphisms and esophageal squamous cell carcinoma susceptibility and prognosis in a Chinese population

https://doi.org/10.1016/j.prp.2017.10.008Get rights and content

Abstract

Objective

This study aims to explore the correlation between X-linked inhibitor of apoptosis protein (XIAP) gene polymorphisms (rs8371 and rs9856) with the susceptibility and prognosis of esophageal squamous cell carcinoma (ESCC), providing a potential treatment for ESCC.

Method

A total of 170 ESCC patients (case group) and 191 healthy people (control group) were enrolled in our study. Genotyping was conducted on the basis of the ligase detection reaction (LDR). The expressions of XIAP polymorphisms were detected. The patients were followed up every three months until death or the last follow-up day. The overall survival (OS) and progression free survival (PFS) were recorded by Kaplan-Meier survival curve, and the relationship between XIAP gene polymorphism and risk and prognosis of ESCC was assessed by Cox multivariate analysis.

Result

TT + CT genotype and T allele frequencies of XIAP rs8371 and rs9856 in the case group were significantly lower compared to those of the control group (all P < 0.05), suggesting that TT + CT genotype of XIAP rs8371 and rs9856 was associated with ESCC susceptibility. XIAP rs8371 and rs9856 polymorphisms were associated with tumor node metastasis (TNM) staging, depth of invasion and lymph node metastasis. The OS and PFS of TT + CT genotype carriers of rs8371 were longer than those of CC genotype carriers. Smoking, alcohol, TNM staging, depth of invasion, and lymph node metastasis were significantly associated with the OS and PFS in ESCC patients. Higher TNM staging, depth of invasion, and presence of lymph node metastasis were independent risk factors, while XIAP rs8371 was an independent protective factor for the prognosis of ESCC patients.

Conclusion

The present study demonstrates that XIAP rs8371 and rs9856 are associated with susceptibility to ESCC, and rs8371 polymorphisms might serve as an indicator for improved clinical efficacy and prognosis of ESCC patients.

Introduction

Esophageal cancer (EC) is a highly aggressive malignancy affecting the upper gastrointestinal tract, which further includes esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) [1]. ESCC is the most common type of EC and the sixth leading cause of cancer-related deaths over the world [2]. In addition, more than 80% of total ESCC cases and deaths occur in the developing countries, among which half occurred in China [3]. Clinically, the symptoms involve dysphagia, a dry cough, adenopathy around the collarbone, weight loss, and hematemesis [4]. Additionally, various factors were found to be involved in the occurrence and development of ESCC, including some genetic factors (alcohol dehydrogenase 1 B and aldehyde dehydrogenase 2 family), environmental factors (smoking, alcohol drinking, and infection of bacteria or virus) and cultural factors (various high-temperature food and long-time stocked rice) [5]. Generally, the common course of treatment for EC is surgery, which is the best curative option for non-metastatic patients; however, EC patients suffer from poor quality of life and prognosis [3]. Therefore, it is trivial to find prognostic biomarkers of EC because of its high incidence and mortality rates in China [4].

The inhibitor of apoptosis proteins (IAPs) family is endogenous proteins with antiapoptotic functions [6]. Amongst the 8 identified human IAPs, X-linked inhibitor of apoptosis protein (XIAP) is one of the most potent inhibitors of apoptosis and an elevated expression of XIAP in many cancers, such as ESCC, is associated with a poor prognosis [7]. Mammalian IAPs suppress the apoptosis of cells by binding or inhibiting caspases or through some caspase-related mechanisms [8]. Besides, XIAP holds great significance for diagnosis and prognosis and also has a key influence in the occurrence and development of various cancers including EC [9], [10]. The relationship between XIAP gene polymorphisms and human diseases, such as lung cancer and hemophagocytic lymphohistiocytosis has been investigated, yet no specific study has precisely explored the correlation between XIAP gene polymorphisms and EC [11], [12]. XIAP rs8371 and rs9856 are two single nucleotide polymorphisms (SNPs) identified in patients with familial pancreatic cancer [13]. Moreover, Flygare JA et al. also demonstrated the overexpression of XIAP in EC [14]. Polymorphisms in the XIAP gene might play an important role in the regulation of the XIAP expression or activity, thereby affecting susceptibility to EC [11]. Therefore, we aim to explore the association between XIAP genetic polymorphisms (rs8371 and rs9856) and ESCC susceptibility and prognosis, which can help in predicting the prognosis and tailoring the treatment accordingly for ESCC patients.

Section snippets

Ethics statement

This study was performed with approval of the Ethics Committee of the Chifeng Municipal Hospital. Written informed consents were acquired from all patients. All personal information, history of diseases, family medical history and gene information obtained in this study was kept strictly confidential. All procedures in this study were performed in strict accordance with the principles of the Declaration of Helsinki.

Study subjects

One hundred and seventy ESCC patients (111 males and 59 females; age:

Genotyping results of rs8371 and rs9856

A laser scanner read the hybridized microarray, and the genotype of rs8371 and rs9856 in XIAP gene are shown in Fig. 1. The first column was the positive reference point, indicating whether there was a problem with the hybridization reaction. There was a signal in the point, highlighting and confirming that the hybridization reaction was normal. Fig. 1A is the rs8371 genotyping result, and Fig. 1B is the rs9856 genotyping result.

Correlation between XIAP gene polymorphisms (rs8371 and rs9856) and ESCC susceptibility in the case and the control groups

The allele frequency and genotype distribution of XIAP rs8371 and

Discussion

Evidence form previous studies have proven that genetic susceptibility and polymorphism are essential in EC, including ESCC and EAC [16], [17]. Therefore, our study aimed at exploring the correlation between XIAP gene polymorphism and EC. Moreover, our study observed that the XIAP rs8371 and rs9856 genetic polymorphisms were correlated with susceptibility to ESCC.

Initially, this study illustrated that the frequency distribution of the TT, TT + CT genotype and T allele of XIAP rs8371 in the case

Conflicts of interest

None.

Acknowledgment

We thank the reviewers for critical comments.

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