Meng Hui, Guan Xingying, Guo Hong, Xiong Gang, Yang Kang, Wang Kai, Bai Yun
Department of Medical Genetics, Third Military Medical University, Chongqing, 400038, China.
Tumour Biol. 2015 Aug;36(8):6231-8. doi: 10.1007/s13277-015-3308-3. Epub 2015 Mar 17.
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers in the world. Epidemiological survey studies have verified that the development of ESCC relates to a complex interactive process between multiple genetic susceptibilities and environmental exposure. Serpins are a broadly distributed family of protease inhibitors and have been recognized as tumor suppressors in multiple cancer types. While previous studies have reported that Serpin polymorphisms are associated with tumorigenesis, the genetic and functional single nucleotide polymorphisms (SNP) in these genes appear to be complex and remain to be elucidated. In this study, a total of 500 ESCC cases and 500 matched controls in a Southwest China population were evaluated for six SNPs in the exons of three Serpin genes (SerpinB5, SerpinB2, and SerpinE1). Among the six SNPs, the C allele of rs2289519 and rs2289520 in SerpinB5 showed decreased risk of ESCC and the variants might interact with smoking status. Haplotype analysis showed that the T-G haplotype (corresponding to rs2289519-rs2289520) increased the risk of ESCC, while the C-C haplotype decreased the risk. We also found that SerpinB5 gene mRNA expression was significantly downregulated in ESCC cell lines and patient specimen while there is no change in protein structure with different haplotypes. Our results demonstrated that the expression of SerpinB5 was downregulated in ESCC, and the positive SNPs might be associated with a risk of ESCC development.
食管鳞状细胞癌（ESCC）是世界上侵袭性最强的癌症之一。流行病学调查研究证实，ESCC的发生与多种遗传易感性和环境暴露之间复杂的相互作用过程有关。丝氨酸蛋白酶抑制剂（Serpins）是一类广泛分布的蛋白酶抑制剂家族，在多种癌症类型中被认为是肿瘤抑制因子。虽然先前的研究报道Serpin多态性与肿瘤发生有关，但这些基因中的遗传和功能性单核苷酸多态性（SNP）似乎很复杂，仍有待阐明。在本研究中，对中国西南地区人群中的500例ESCC病例和500例匹配对照进行了三个Serpin基因（SerpinB5、SerpinB2和SerpinE）外显子中六个SNP的评估。在这六个SNP中，SerpinB5中rs2289519和rs2289520的C等位基因显示ESCC风险降低，且这些变异可能与吸烟状况相互作用。单倍型分析表明，T-G单倍型（对应于rs2289519-rs2289520）增加了ESCC风险，而C-C单倍型降低了风险。我们还发现，SerpinB5基因mRNA表达在ESCC细胞系和患者标本中显著下调，而不同单倍型的蛋白质结构没有变化。我们的结果表明，SerpinB5在ESCC中表达下调，阳性SNP可能与ESCC发生风险相关。
