Parkin deficiency promotes liver cancer metastasis by TMEFF1 transcription activation via TGF-β/Smad2/3 pathway  

作　　者：Qi Su Jing-jing Wang Jia-yan Ren Qing Wu Kun Chen Kai-hui Tu Yu Zhang Sze Wei Leong Ammar Sarwar Xu Han Mi Zhang Wei-feng Dai Yan-min Zhang 

机构地区：[1]School of Pharmacy,Health Science Center,Xi’an Jiaotong University,Xi’an,710061,China [2]Department of Chemistry,Faculty of Science,Universiti Malaya,50603,Kuala Lumpur,Malaysia [3]Faculty of Life Science and Technology,Kunming University of Science and Technology,Kunming,650500,China

出　　处：《Acta Pharmacologica Sinica》2024年第7期1520-1529,共10页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China (Grant 81903643 and 82374095);the National Natural Science Foundation of Shaanxi Province (2024JC-YBQN-0891);the Shaanxi Province Science Fund for Distinguished Young Scholars (2023-JC-JQ-59);the Shaanxi Province Science and Technology Development Plan Project (2022ZDLSF05-05).

摘　　要：Parkin(PARK2)deficiency is frequently observed in various cancers and potentially promotes tumor progression.Here,we showed that Parkin expression is downregulated in liver cancer tissues,which correlates with poor patient survival.Parkin deficiency in liver cancer cells promotes migration and metastasis as well as changes in EMT and metastasis markers.A negative correlation exists between TMEFF1 and Parkin expression in liver cancer cells and tumor tissues.Parkin deficiency leads to upregulation of TMEFF1 which promotes migration and metastasis.TMEFF1 transcription is activated by Parkin-induced endogenous TGF-βproduction and subsequent phosphorylation of Smad2/3 and its binding to TMEFF1 promotor.TGF-βinhibitor and TMEFF1 knockdown can reverse shParkin-induced cell migration and changes of EMT markers.Parkin interacts with and promotes the ubiquitin-dependent degradation of HIF-1α/HIF-1βand p53,which accounts for the suppression of TGF-βproduction.Our data have revealed that Parkin deficiency in cancer leads to the activation of the TGF-β/Smad2/3 pathway,resulting in the expression of TMEFF1 which promotes cell migration,EMT,and metastasis in liver cancer cells.

关 键 词：PARKIN TMEFF1 TGF-β/Smad2/3 transcription activation HIF-1a/HIF-1β p53 

分 类 号：R96[医药卫生—药理学]