Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Environ Mol Mutagen. 2021 Apr;62(4):273-283. doi: 10.1002/em.22432. Epub 2021 Mar 22.
The T-cell immunoglobulin and mucin domain containing molecule 3 (TIM-3), a crucial immune regulatory molecule, is an emerging immune checkpoint target for cancer therapy. Our study aimed to investigate the association between TIM-3 polymorphisms (rs10053538 C > A, rs10515746 C > A, and rs1036199 A > C) and the susceptibility and prognosis of esophageal squamous cell carcinoma (ESCC). We further detect the effects of polymorphisms on TIM-3 expression. Two independent case-control sets (population-based and hospital-based sets) were performed in total 994 ESCC patients and 998 controls. TIM-3 polymorphisms were genotyped by polymerase chain reaction-ligase detection reaction (PCR). Survival data were available for 198 patients who received platinum-based chemotherapy after surgery. The regulation on TIM-3 expression by the polymorphisms was investigated in 35 patients using real-time quantitative PCR. The association between mRNA level of TIM-3 and survival was detected by using Kaplan-Meier plotter database. We found that for rs10053538 C > A polymorphisms, A allele was associated with significant increased risk of ESCC (odds ratios [OR] = 1.34, 95%CI = 1.05-1.72), and CA/AA genotypes enhanced susceptibility to ESCC for smokers (adjusted OR = 1.61, 95%CI = 1.00-2.59). The patients with AA genotypes had significantly poor prognosis (adjusted HR = 4.98, 95%CI = 1.14-21.71). The patients carrying CA/AA genotypes had significantly higher mRNA levels of TIM-3 than those carrying the CC genotype. Furthermore, high mRNA level of TIM-3 had a shorter overall survival in patients (HR = 2.56, 95%CI = 1.04-6.28). For rs10515746 C > A and rs1036199 A > C polymorphisms, there were no statistical correlation with the progression of ESCC. These data demonstrate that rs10053538 C > A polymorphisms may be associated with the susceptibility and prognosis of ESCC patients through regulating expression of TIM-3.
T 细胞免疫球蛋白和粘蛋白结构域包含分子 3（TIM-3）是一种重要的免疫调节分子，是癌症治疗中新兴的免疫检查点靶点。我们的研究旨在探讨 TIM-3 多态性（rs10053538 C > A、rs10515746 C > A 和 rs1036199 A > C）与食管鳞状细胞癌（ESCC）易感性和预后的关系。我们进一步检测了多态性对 TIM-3 表达的影响。总共在 994 名 ESCC 患者和 998 名对照中进行了两项独立的病例对照研究（基于人群和基于医院的研究）。通过聚合酶链反应-连接酶检测反应（PCR）对 TIM-3 多态性进行基因分型。对 198 名接受手术后铂类化疗的患者进行了生存数据分析。在 35 名患者中使用实时定量 PCR 研究了多态性对 TIM-3 表达的调控。通过 Kaplan-Meier 绘图器数据库检测 TIM-3 mRNA 水平与生存的关系。我们发现，对于 rs10053538 C > A 多态性，A 等位基因与 ESCC 的显著高风险相关（比值比[OR] = 1.34，95%CI = 1.05-1.72），CA/AA 基因型增加了吸烟者患 ESCC 的易感性（调整 OR = 1.61，95%CI = 1.00-2.59）。AA 基因型患者的预后明显较差（调整 HR = 4.98，95%CI = 1.14-21.71）。携带 CA/AA 基因型的患者 TIM-3 的 mRNA 水平明显高于携带 CC 基因型的患者。此外，TIM-3 高 mRNA 水平的患者总生存期明显缩短（HR = 2.56，95%CI = 1.04-6.28）。对于 rs10515746 C > A 和 rs1036199 A > C 多态性，与 ESCC 的进展没有统计学相关性。这些数据表明，rs10053538 C > A 多态性可能通过调节 TIM-3 的表达与 ESCC 患者的易感性和预后相关。
