Zheng Chao, Luo Jiaqian, Yang Yifan, Dong Rui, Yu Fa-Xing, Zheng Shan
Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.
Institute of Pediatrics, Children's Hospital of Fudan University and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Front Pediatr. 2021 Jan 21;8:618226. doi: 10.3389/fped.2020.618226. eCollection 2020.
Biliary atresia (BA), an inflammatory destruction of the bile ducts, leads to liver fibrosis in infants and accounts for half of cases undergoing pediatric liver transplantation. Yes-associated protein (YAP), an effector of the Hippo signaling pathway, is critical in maintaining identities of bile ductal cells. Here, we evaluated the expression of YAP and YAP target genes in BA livers and a rhesus rotavirus (RRV)-induced BA mice model. Liver specimens collected from 200 BA patients were compared with those of 30 non-BA patients. Model mice liver tissues were also collected. The expression of YAP and YAP target genes were measured by transfection, RNA-seq, immunohistochemistry, immunoblot, and quantitative PCR. Masson's trichrome staining and the Biliary Atresia Research Consortium (BARC) system were utilized to score liver fibrosis status. The expression of YAP is elevated and positively correlated with fibrosis in BA livers. Moreover, , which is identified as the target gene of YAP, is also highly expressed in BA livers. Consistent with clinical data, YAP and ANKRD1 are significantly upregulated in RRV-induced BA mouse model. YAP expression is closely correlated with the bile duct hyperplasia and liver fibrosis, and may serve as an indicator for liver fibrosis and BA progression. This study indicates an involvement of the Hippo signaling pathway in the development of BA, and the YAP induced ANKRD1 expression may also be related to bile duct hyperplasia in BA. This provides a new direction for more in-depth exploration of the etiology and pathogenesis of biliary atresia.
胆道闭锁（BA）是一种胆管的炎性破坏疾病，可导致婴儿肝纤维化，且占小儿肝移植病例的一半。Yes相关蛋白（YAP）是Hippo信号通路的效应器，对维持胆管细胞的特性至关重要。在此，我们评估了YAP及其靶基因在BA肝脏和恒河猴轮状病毒（RRV）诱导的BA小鼠模型中的表达。将收集的200例BA患者的肝脏标本与30例非BA患者的标本进行比较。同时也收集模型小鼠的肝脏组织。通过转染、RNA测序、免疫组织化学、免疫印迹和定量PCR检测YAP及其靶基因的表达。采用Masson三色染色法和胆道闭锁研究联盟（BARC）系统对肝纤维化状态进行评分。YAP在BA肝脏中的表达升高，且与纤维化呈正相关。此外，被确定为YAP靶基因的ANKRD1在BA肝脏中也高表达。与临床数据一致，YAP和ANKRD1在RRV诱导的BA小鼠模型中显著上调。YAP表达与胆管增生和肝纤维化密切相关，可能作为肝纤维化和BA进展的一个指标。本研究表明Hippo信号通路参与了BA的发生发展，YAP诱导的ANKRD1表达也可能与BA中的胆管增生有关。这为更深入探究胆道闭锁的病因和发病机制提供了新方向。
