Splicing factor PTBP1 promotes hepatocarcinogenesis via oncogenic splice-switching of MAPT  

作　　者：WENYING ZHENG YANYAN SHANG KAI DU AILING LUO LIJUN PEI MEIQI LI GUOPING ZHANG MIN DENG 

机构地区：[1]Guangzhou Institute of Cancer Research,The Affiliated Cancer Hospital,Guangzhou Medical University,Guangzhou,510095,China [2]Medical Oncology,Yuebei People Hospital,Shaoguan,512026,China

出　　处：《Oncology Research》2025年第5期1121-1133,共13页肿瘤学研究(英文)

基　　金：supported by the National Natural Science Foundation of China(Nos.81972771,82173062);the Key Areas Project of Education Department of Guangdong Province(No.2021ZDZX2017);the Tertiary Education Scientific Research Project of Guangzhou Municipal Education Bureau(No.202235387);the Guangzhou Science and Technology Project of Guangzhou Municipal Science and Technology Bureau(No.2023A03J0428);the Natural Science Foundation of Guangdong Province,China(No.2024A1515013082);the Guangdong Basic and Applied Basic Research 21 Foundation(No.2021A1515010403).

摘　　要：Background:Alterations in splicing factors contribute to aberrant alternative splicing(AS),which subsequently promotes tumor progression.The splicing factor polypyrimidine tract binding protein 1(PTBP1)has been shown to facilitate cancer progression by modulating oncogenic variants.However,its specific role and underlying mechanisms in hepatocellular carcinoma(HCC)remain to be elucidated.Methods:PTBP1 expression was evaluated in HCC tissues and cell lines.Subsequently,cells were transfected with vectors designed for PTBP1 overexpression or downregulation.The biological function of PTBP1 was assessed in vitro and in vivo using MTS assays,colony formation assays,transwell assays,xenograft formation,tail vein injection,and orthotopic models.Transcriptome analysis was conducted to elucidate the underlying molecular mechanisms.Results:Our findings demonstrated that PTBP1 exhibited elevated expression in HCC cell lines and tissues.Furthermore,its expression positively correlated with overall and disease-free survival rates,as well as tumor grade and stage.PTBP1 knockdown reduced HCC cell proliferation,migration,and invasion in vitro and suppressed hepatocarcinoma xenograft growth and infiltration in vivo.RNA sequencing(RNA-Seq)analysis identified the AS events associated with PTBP1.PTBP1 functionally enhanced cell proliferation,invasion,and migration by modulating the AS of the microtubule-associated protein tau(MAPT)gene and promoting oncogene expression.Notably,the dysregulation of MAPT splicing coincided with increased PTBP1 expression in HCC.Conclusions:PTBP1-guided AS of the MAPT gene enhances tumorigenicity in HCC through activation of the MAPK/ERK pathways.

关 键 词：Hepatocellular carcinoma Alternative splicing PTBP1 MAPT 

分 类 号：R735.7[医药卫生—肿瘤]