Transcriptional repression and apoptosis influence the effect of APOBEC3A/3B functional polymorphisms on biliary tract cancer risk. Transcriptional repression and apoptosis influence the effect of APOBEC3A/3B functional polymorphisms on biliary tract cancer risk

APOBEC3s-related somatic mutations are the predominant burden in biliary tract cancers (BTCs). Here, we reveal the effects and mechanisms of APOBEC3A/3B functional polymorphisms on cholangiocarcinoma and gallbladder cancer (GBC). rs2267401-G at the APOBEC3B promoter decreases cholangiocarcinoma risk but increased GBC risk. rs2267401-G confers a decreased APOBEC3B promoter activity in cholangiocarcinoma cells but an increased activity in GBC cells. rs12157810-C at the APOBEC3A promoter decreases the risk of BTCs. rs12157810-C up-regulated the promoter activity in both cells. APOBEC3A overexpression attenuates cancer evolution via causing apoptosis, in contrast to APOBEC3B. Inflammatory factors promote cancer evolution via interacting with transcriptional repressors regulating the APOBEC3A/3B promoters. ATAC-seq was used to identify the difference between transcriptional networks of cholangiocarcinoma and GBC. Overall design: 4 Cell lines were involved in the single-cell ATAC-seq analysis: the cholangiocarcinoma cell line RBE, the RBE with stimulation of TNF-a, GBC, and GBC with stimulation of TNF-a

载脂蛋白B mRNA编辑酶催化多肽样3家族（APOBEC3s）相关体细胞突变是胆道恶性肿瘤（biliary tract cancers, BTCs）的主要突变负荷。本研究阐明了APOBEC3A/3B功能多态性对胆管癌与胆囊癌（gallbladder cancer, GBC）的影响及作用机制。位于APOBEC3B启动子区域的rs2267401-G位点可降低胆管癌患病风险，却升高胆囊癌患病风险。rs2267401-G可降低胆管癌细胞中APOBEC3B的启动子活性，却在胆囊癌细胞中提升该启动子活性。位于APOBEC3A启动子区域的rs12157810-C位点可降低胆道恶性肿瘤的患病风险。rs12157810-C可在两种细胞系中上调启动子活性。与APOBEC3B不同，APOBEC3A过表达可通过诱导细胞凋亡抑制肿瘤进展。炎症因子可通过结合调控APOBEC3A/3B启动子的转录抑制因子，进而促进肿瘤进展。本研究采用转座酶可及性染色质测序（ATAC-seq）技术，鉴定胆管癌与胆囊癌的转录调控网络差异。整体实验设计：本研究的单细胞ATAC-seq分析共涉及4株细胞系：胆管癌细胞系RBE、经肿瘤坏死因子α（tumor necrosis factor α, TNF-α）刺激的RBE细胞、胆囊癌细胞系GBC，以及经TNF-α刺激的GBC细胞。