西安交通大学Yan-min Zhang团队发现，Parkin缺乏通过TGF-β/Smad2/3途径激活TMEFF1转录来促进肝癌转移。相关论文于2024年3月22日在线发表于国际学术期刊《中国药理学报》。

研究人员发现肝癌组织中的Parkin表达下调，这与患者生存率低有关。肝癌细胞中Parkin的缺乏会促进迁移和转移，以及EMT和转移标记物的变化。肝癌细胞和肿瘤组织中TMEFF1和Parkin的表达呈负相关。Parkin缺乏会导致TMEFF1上调，从而促进迁移和转移。TMEFF1的转录是由Parkin诱导的内源性TGF-β产生，和随后的Smad2/3磷酸化及其与TMEFF1启动子的结合激活的。

TGF-β抑制剂和TMEFF1基因敲除，可逆转shParkin诱导的细胞迁移和EMT标记物的变化。Parkin与HIF-1α/HIF-1β和p53相互作用并促进泛素依赖性降解，从而抑制了TGF-β的产生。这些数据显示，癌症患者缺乏Parkin会导致TGF-β/Smad2/3通路被激活，导致TMEFF1的表达，从而促进肝癌细胞的迁移、EMT和转移。

据了解，Parkin（PARK2）缺乏经常在各种癌症中出现，并有可能促进肿瘤的进展。

附：英文原文

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

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

Issue&Volume: 2024-03-22

Abstract: Parkin (PARK2) deficiency is frequently observed in various cancers and potentially promotes tumor progression. Here, we showed that Parkin expression is down regulated 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-β production and subsequent phosphorylation of Smad2/3 and its binding to TMEFF1 promotor. TGF-β inhibitor 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-1β and p53, which accounts for the suppression of TGF-β production. 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.

DOI: 10.1038/s41401-024-01254-3

Source: https://www.nature.com/articles/s41401-024-01254-3