Li Pengyu, Dong Jiacheng, Li Yuan, Yan Jiang, Wang Jiawei, Cao Shuqing, Cao Wei, Zhao Xinyu, Xue Ao, Xu Zekuan, Yang Li
Department of General Surgery, the First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China.
Department of General Surgery, Liyang People's Hospital, Liyang Branch Hospital of Jiangsu Province Hospital, Liyang, 213300, Jiangsu Province, China.
Gastric Cancer. 2025 May;28(3):326-343. doi: 10.1007/s10120-025-01598-7. Epub 2025 Feb 24.
Single nucleotide polymorphisms (SNPs) are associated with various diseases, including gastric cancer. The ADAMTS14 gene is linked to multiple types of cancer. However, the relationship between ADAMTS14 and its genetic polymorphisms with susceptibility to gastric cancer (GC) and prognosis remains unclear.
A case-control study was conducted involving 855 patients diagnosed with gastric cancer (GC) and an equal number of cancer-free controls. Following rigorous statistical analysis, molecular experiments were performed to elucidate the functional significance of the SNPs in the context of GC.
ADAMTS14 rs3740440 (OR = 1.45, p = 0.014) shows a significant association with increased GC risk, while rs11572 (OR = 0.42, p < 0.001) is associated with protection against GC. Moreover, patients with the (CG + GG) genotype of rs3740440 exhibit a poor prognosis (HR = 1.68, p = 0.007). Mechanistically, luciferase reporter assays revealed that the G allele of rs3740440 disrupts the binding of hsa-miR-4294 and hsa-miR-3198 to the 3' untranslated region (3' UTR) of ADAMTS14, leading to increased expression of ADAMTS14 and the promotion of malignant behaviors in GC cells.
Our findings underscore the significant role of ADAMTS14 SNPs in both the risk and prognosis of gastric cancer (GC), providing valuable insights into the underlying molecular mechanisms. Specifically, rs3740440 disrupts the interaction between ADAMTS14 and miRNA, resulting in increased expression of ADAMTS14. This heightened expression enhances its malignant biologic behaviors, indicating that rs3740440 could be a potential predictive marker for gastric cancer risk and prognosis.
单核苷酸多态性（SNP）与包括胃癌在内的多种疾病相关。ADAMTS14基因与多种类型的癌症有关。然而，ADAMTS14及其基因多态性与胃癌（GC）易感性和预后之间的关系仍不清楚。
进行了一项病例对照研究，纳入855例被诊断为胃癌（GC）的患者和数量相等的无癌对照。经过严格的统计分析后，进行分子实验以阐明SNP在GC背景下的功能意义。
ADAMTS14 rs3740440（OR = 1.45，p = 0.014）与GC风险增加显著相关，而rs11572（OR = 0.42，p < 0.001）与预防GC相关。此外，rs3740440的（CG + GG）基因型患者预后较差（HR = 1.68，p = 0.007）。机制上，荧光素酶报告基因检测显示rs3740440的G等位基因破坏了hsa-miR-4294和hsa-miR-3198与ADAMTS14的3'非翻译区（3'UTR）的结合，导致ADAMTS14表达增加并促进GC细胞中的恶性行为。
我们的研究结果强调了ADAMTS14 SNP在胃癌（GC）风险和预后中的重要作用，为潜在的分子机制提供了有价值的见解。具体而言，rs3740440破坏了ADAMTS14与miRNA之间的相互作用，导致ADAMTS14表达增加。这种表达增加增强了其恶性生物学行为，表明rs3740440可能是胃癌风险和预后的潜在预测标志物。
