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

Qi Su1, Jing-jing Wang1, Jia-yan Ren1, Qing Wu1, Kun Chen1, Kai-hui Tu1, Yu Zhang1, Sze Wei Leong2, Ammar Sarwar1, Xu Han1, Mi Zhang3, Wei-feng Dai3, Yan-min Zhang1
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
Correspondence to: Yan-min Zhang:,
DOI: 10.1038/s41401-024-01254-3
Received: 23 October 2023
Accepted: 26 February 2024
Advance online: 22 March 2024


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-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.

Keywords: Parkin; TMEFF1; TGF-β/Smad2/3; transcription activation; HIF-1α/HIF-1β; p53

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