Background and Aims:Hepatoblastoma (HBL) and fibrolamellar hepatocellular carcinoma (FLC) are the most common liver malignancies in children and young adults. FLC oncogenesis is associated with the generation of the fusion kinase, DNAJB1-PKAc (J-PKAc). J-PKAc has been found in 90% of FLC patients’ tumors but not in other liver cancers. Since previous studies of J-PKAc were performed with adolescent patients, we asked if young children may express J-PKAc and if there are consequences of such expression.Methods:The biobank of the pediatric HBL/HCN-NOS specimens was examined by QRT-PCR, Western blots, RNA-Seq, and immunostaining with fusion-specific antibodies.Results:J-PKAc is expressed in 70% of the HBL/HCN-NOS patients. RNA-Seq analysis revealed that HBL tumors that do not have cells expressing J-PKAc show elevated expression of the membrane attack complex (MAC), which eliminates cells expressing J-PKAc. The fusion-positive HBL/HCN-NOS samples have several signaling pathways that are different from fusion-negative HBLs. Upregulated pathways included genes involved in the G1 to S transition and in liver cancer. Downregulated pathways included over 60 tumor suppressors, the CYP family, and the SLC family. The repression of these genes involves J-PKAc-β-catenin-TCF4-mediated elevation of the HDAC1-Sp5 pathway. The identified upregulated and downregulated pathways are direct targets of the fusion kinase. The J-PKAc kinase is also detected in livers of 1-year-old children with biliary atresia (BA).Conclusions:J-PKAc is expressed in both HBL tumor and BA liver samples, contributing to the development of HBL and creating a transcriptome profiling consistent with the potential development of liver cancer in young patients.
背景与目的：肝母细胞瘤（HBL）和纤维板层肝细胞癌（FLC）是儿童及青少年中最常见的肝脏恶性肿瘤。FLC的肿瘤发生与融合激酶DNAJB1-PKAc（J-PKAc）的产生相关。研究发现，90%的FLC患者肿瘤中存在J-PKAc，而其他类型肝癌中则未检测到。由于既往对J-PKAc的研究主要基于青少年患者，本研究旨在探究幼儿是否可能表达J-PKAc，以及这种表达可能带来的影响。 方法：通过实时定量聚合酶链反应、蛋白质印迹法、RNA测序及融合特异性抗体免疫染色技术，对儿童HBL/肝细胞肿瘤非特指型（HCN-NOS）样本库进行检测分析。 结果：70%的HBL/HCN-NOS患者样本中检测到J-PKAc表达。RNA测序分析显示，不表达J-PKAc的HBL肿瘤中膜攻击复合物（MAC）表达升高，该复合物可清除表达J-PKAc的细胞。融合阳性HBL/HCN-NOS样本中存在多条与融合阴性HBL不同的信号通路。上调通路包括参与G1期向S期转换及肝癌相关的基因；下调通路则涉及60余种肿瘤抑制基因、CYP家族及SLC家族。这些基因的抑制与J-PKAc-β-catenin-TCF4介导的HDAC1-Sp5通路激活有关。已识别的上调和下调通路均为该融合激酶的直接作用靶点。此外，在1岁胆道闭锁（BA）患儿的肝脏中也检测到J-PKAc激酶。 结论：J-PKAc在HBL肿瘤及BA肝脏样本中均有表达，其不仅促进HBL的发展，还形成与年轻患者肝癌潜在发生相一致的转录组特征谱。
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