Yin Jie, Wang Lan, Zhu Ji-Min, Yu Qian, Xue Ru-Yi, Fang Ying, Zhang Yi-An, Chen Yan-Jie, Liu Tao-Tao, Dong Ling, Shen Xi-Zhong
Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China.
Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Shanghai, China.
Oncotarget. 2016 Apr 19;7(16):21939-51. doi: 10.18632/oncotarget.7877.
Pre-mRNA processing factor 19 (Prp19) is involved in many cellular events including pre-mRNA processing and DNA damage response. However, the pathological role of Prp19 in hepatocellular carcinoma (HCC) is still elusive. Here, we reported that Prp19 was increased in most HCC tissues and HCC cell lines, and its overexpression in HCC tissues was positively correlated with vascular invasion, tumor capsule breakthrough and poor prognosis. Prp19 potentiated migratory and invasive abilities of HCC cells in vitro and in vivo. Furthermore Prp19 facilitated Twist1-induced epithelial-mesenchymal transition. Mechanistic insights revealed that Prp19 directly binded with TGF-β-activated kinase1 (TAK1) and promoted the activation of p38 mitogen-activated protein kinase (MAPK), preventing Twist1 from degradation. Finally Prp19/p38 MAPK/Twist1 axis was attested in nude mice xenografts and HCC patient specimens. This work implies that the gain of Prp19 is a critical event during the progression of HCC, making it a promising target for malignancies with aberrant Prp19 expression.
前体mRNA加工因子19（Prp19）参与包括前体mRNA加工和DNA损伤反应在内的许多细胞事件。然而，Prp19在肝细胞癌（HCC）中的病理作用仍不清楚。在此，我们报道Prp19在大多数HCC组织和HCC细胞系中表达增加，其在HCC组织中的过表达与血管侵犯、肿瘤包膜突破及不良预后呈正相关。Prp19在体外和体内均增强了HCC细胞的迁移和侵袭能力。此外，Prp19促进了Twist1诱导的上皮-间质转化。机制研究表明，Prp19直接与转化生长因子-β激活激酶1（TAK1）结合并促进p38丝裂原活化蛋白激酶（MAPK）的激活，从而防止Twist1降解。最后，在裸鼠异种移植瘤和HCC患者标本中证实了Prp19/p38 MAPK/Twist1轴。这项工作表明，Prp19的增加是HCC进展过程中的一个关键事件，使其成为Prp19表达异常的恶性肿瘤的一个有希望的靶点。
