Department of Biochemistry, The Catholic University of Korea, College of Medicine, Seoul, South Korea.
Institute of Aging and Metabolic Diseases, The Catholic University of Korea, College of Medicine, Seoul, South Korea.
J Pathol. 2019 Nov;249(3):395-408. doi: 10.1002/path.5325. Epub 2019 Aug 27.
Polypyrimidine tract-binding protein 1 (PTBP1) is one of the most investigated multifunctional RNA-binding proteins (RBP), controlling almost all steps of mRNA metabolism and processing. It has been reported that PTBP1 is overexpressed in many different types of cancer and this high expression is associated with increased proliferation and poor prognoses. However, there are no reports on a putative role for PTBP1 in the molecular abnormalities and pathogenesis of hepatocellular carcinoma (HCC). Here, we identified PTBP1 as a positive regulator of human HCC growth. The expression of PTBP1 was increased in human HCC cells and tissues compared to the corresponding controls, and this high expression was positively correlated with increased tumor size and a reduced survival rate. Mechanistically, PTBP1 enhanced cyclin D3 (CCND3) translation by interacting with the 5'-untranslated region (5'-UTR) of CCND3 mRNA, consequently facilitating cell cycle progression and tumor growth. Furthermore, we found that miR-194 inhibits PTBP1 expression by binding to the 3'-UTR of PTBP1 mRNA, resulting in reduced CCND3 levels and HCC cell growth; moreover, the levels of PTBP1 were negatively correlated with miR-194 levels in HCC. Taken together, these findings identify PTBP1 as a pivotal enhancer of HCC growth; the miR-194/PTBP1/CCND3 axis seemingly has a crucial role in the development and progression of HCC and targeting the axis could be a novel therapeutic strategy against human HCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
多嘧啶 tract 结合蛋白 1（PTBP1）是研究最多的多功能 RNA 结合蛋白（RBP）之一，它控制着 mRNA 代谢和加工的几乎所有步骤。已经报道 PTBP1 在许多不同类型的癌症中过度表达，并且这种高表达与增殖增加和预后不良相关。然而，目前尚无关于 PTBP1 在肝细胞癌（HCC）的分子异常和发病机制中的作用的报道。在这里，我们鉴定出 PTBP1 是人类 HCC 生长的正调节剂。与相应对照相比，PTBP1 在人 HCC 细胞和组织中的表达增加，并且这种高表达与肿瘤大小增加和生存率降低呈正相关。从机制上讲，PTBP1 通过与 CCND3 mRNA 的 5'-非翻译区（5'-UTR）相互作用增强了细胞周期蛋白 D3（CCND3）的翻译，从而促进了细胞周期进程和肿瘤生长。此外，我们发现 miR-194 通过结合 PTBP1 mRNA 的 3'-UTR 抑制 PTBP1 的表达，导致 CCND3 水平降低和 HCC 细胞生长；此外，在 HCC 中，PTBP1 的水平与 miR-194 的水平呈负相关。总之，这些发现确定了 PTBP1 作为 HCC 生长的关键增强子；miR-194/PTBP1/CCND3 轴似乎在 HCC 的发展和进展中具有关键作用，针对该轴可能是针对人类 HCC 的一种新的治疗策略。©2019 英国和爱尔兰病理学学会。由 John Wiley & Sons，Ltd. 出版。
