Dong Rui, Yang Yifan, Shen Zhen, Zheng Chao, Jin Zhu, Huang Yanlei, Zhang Zhien, Zheng Shan, Chen Gong
Department of Pediatric Surgery, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China.
Cell Death Dis. 2017 Mar 30;8(3):e2719. doi: 10.1038/cddis.2017.99.
Biliary atresia is a rare, devastating disease of infants where a fibroinflammatory process destroys the bile ducts, leading to fibrosis and biliary cirrhosis, and death if untreated. The cause and pathogenesis remain largely unknown. We tried to investigate factors involved in biliary atresia, especially forkhead box A3 (Foxa3), which might exert a role in the treatment of liver disease. We used RNA sequencing to sequence the whole transcriptomes of livers from six biliary atresia and six choledochal cysts patients. Then, we employed a rat disease model by bile duct ligation (BDL) and adenovirus transduction to address the function of Foxa3 in biliary atresia. We found that tight junction, adherence junction, cell cycle, apoptosis, chemokine singling, VEGF and MAPK signaling pathways were enriched in biliary atresia livers. We showed that Foxa3 expression was notably decreased in liver samples from biliary atresia patients. More importantly, we found that its lower expression predicted a poorer overall survival of biliary atresia patients. Rats that received BDL surgery and Foxa3 expression adenovirus resulted in a significant decrease in the deposition of collagen, and expression of profibrotic cytokines (transforming growth factor-β and connective tissue growth factor) and fibrosis markers (α-smooth muscle actin, collagen I and collagen III), as compared with rats that received BDL surgery and control adenovirus. Our data suggested a protection role for Foxa3 during the progression of liver fibrosis in biliary atresia, and thereby supported increasing Foxa3 as a targeted treatment strategy.
胆道闭锁是一种罕见的、严重的婴儿疾病，其纤维炎性过程会破坏胆管，导致纤维化和胆汁性肝硬化，若不治疗则会导致死亡。其病因和发病机制在很大程度上仍不清楚。我们试图研究与胆道闭锁相关的因素，特别是叉头框A3（Foxa3），它可能在肝病治疗中发挥作用。我们使用RNA测序对6例胆道闭锁患者和6例胆总管囊肿患者的肝脏全转录组进行测序。然后，我们通过胆管结扎（BDL）和腺病毒转导建立大鼠疾病模型，以研究Foxa3在胆道闭锁中的功能。我们发现紧密连接、黏附连接、细胞周期、凋亡、趋化因子信号传导、VEGF和MAPK信号通路在胆道闭锁肝脏中富集。我们发现胆道闭锁患者肝脏样本中Foxa3表达显著降低。更重要的是，我们发现其低表达预示着胆道闭锁患者总体生存率较差。与接受BDL手术和对照腺病毒的大鼠相比，接受BDL手术和Foxa3表达腺病毒的大鼠胶原沉积、促纤维化细胞因子（转化生长因子-β和结缔组织生长因子）和纤维化标志物（α-平滑肌肌动蛋白、I型胶原和III型胶原）的表达显著降低。我们的数据表明Foxa3在胆道闭锁肝纤维化进展过程中具有保护作用，从而支持增加Foxa3作为一种靶向治疗策略。
