Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, Guangzhou Road, Nanjing 210029, China; Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Jiefang Road, Zhenjiang 212001, China.
Department of Medical Oncology, Affiliated Hospital of Jiangsu University, Jiefang Road, Zhenjiang 212001, China.
Gene. 2019 Oct 20;716:144034. doi: 10.1016/j.gene.2019.144034. Epub 2019 Aug 1.
Outcome in adjuvant chemotherapy of gastric cancer (GC) has considerable stage-independent variability, which underscores the need for prognostic or predictive molecular markers. CHAF1A promotes tumor growth while its impact on chemotherapy outcome remains unknown.
CHAF1A protein expression was measured in independent discovery and validation sets that included 86 and 325 patients respectively who received fluoropyrimidines-based adjuvant chemotherapy after radical gastrectomy. The chemosensitizing effect of CHAF1A knockdown was investigated in vitro. Bioinformatics analysis based on RNA-seq and proteome data from public database was performed to investigate the potential mechanisms and further validation was conducted.
In both the discovery and validation sets, CHAF1A expression level was an independent predictor for disease-free survival (HR = 4.25; 95% CI: 2.31-7.79; P < 0.001; and HR = 1.91; 95% CI: 1.03-3.54; P = 0.039, respectively) and overall survival (HR = 3.25; 95% CI: 1.75-6.05; P < 0.001; and HR = 2.42; 95% CI: 1.12-5.20; P = 0.024, respectively) in patients with non-cardia GC but not in those with cardia GC. In GC cells, CHAF1A knockdown significantly decreased the IC of 5-FU. Bioinformatics analyses indicated that CHAF1A correlated with folate metabolism and the expression of thymidylate synthetase (TS). Furthermore, CHAF1A knockdown significantly reduced TS expression in GC cells and CHAF1A positively correlated with TS protein expression in tumor tissues. Finally, ten proteins potentially relevant to the regulation of TS expression by CHAF1A were identified using online tools based on RNA-seq and proteome data.
CHAF1A may impact adjuvant chemotherapy outcome of GC by regulating the expression of TS.
胃癌（GC）辅助化疗的结果具有相当大的与分期无关的可变性，这突显了对预后或预测性分子标志物的需求。CHAF1A 促进肿瘤生长，但其对化疗结果的影响尚不清楚。
在独立的发现和验证集（分别包括 86 例和 325 例接受根治性胃切除术后基于氟嘧啶的辅助化疗的患者）中测量 CHAF1A 蛋白表达。在体外研究 CHAF1A 敲低的化疗增敏作用。基于公共数据库中的 RNA-seq 和蛋白质组数据进行生物信息学分析，以研究潜在机制，并进行进一步验证。
在发现和验证集，CHAF1A 表达水平是无病生存（HR=4.25；95%CI：2.31-7.79；P<0.001；和 HR=1.91；95%CI：1.03-3.54；P=0.039）和总生存（HR=3.25；95%CI：1.75-6.05；P<0.001；和 HR=2.42；95%CI：1.12-5.20；P=0.024）的独立预测因素，而非贲门 GC 患者，但不是贲门 GC 患者。在 GC 细胞中，CHAF1A 敲低显著降低了 5-FU 的 IC。生物信息学分析表明，CHAF1A 与叶酸代谢和胸苷酸合成酶（TS）的表达相关。此外，CHAF1A 敲低显著降低了 GC 细胞中 TS 的表达，并且 CHAF1A 与肿瘤组织中 TS 蛋白表达呈正相关。最后，使用基于 RNA-seq 和蛋白质组数据的在线工具鉴定了十个可能与 CHAF1A 调节 TS 表达相关的蛋白质。
CHAF1A 可能通过调节 TS 的表达来影响 GC 的辅助化疗结果。
