Reply to correspondence 2 on “MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation” Ji Eun Han, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun Clinical and Molecular Hepatology.2026; 32(1): e121. CrossRef
Reply to correspondence 1 on “MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation” Many Sze Man Chan, Terence Kin Wah Lee Clinical and Molecular Hepatology.2026; 32(1): e119. CrossRef
Background/Aims Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and abnormal MET expression plays a crucial role in its progression. However, the specific pathogenic mechanisms of MET in HCC have yet to be fully elucidated. This study aimed to uncover the oncogenic mechanisms of MET in HCC and explore potential therapeutic implications.
Methods Transcriptomic data from the HTVi MET/β-catenin HCC model and GSEA results from TCGA LIHC cohorts were analyzed to identify key genes in HCC development. In vitro assays and in vivo models were used to investigate the role of TRIB3 in HCC progression. Immunofluorescence, co-IP, qRT-PCR, and WB revealed target genes regulated by TRIB3. An AAV8-shTRIB3 construct was developed and we assessed its therapeutic potential.
Results MET promoted HCC development both in vitro and in vivo by upregulating the oncogenic protein TRIB3. Mechanistically, MET transcriptionally activated TRIB3 via the ERK/SP1 axis. TRIB3 then recruited the E3 ubiquitin ligase COP1, which facilitated the ubiquitination and degradation of the tumor suppressor transcription factor FOXO1. TRIB3-mediated FOXO1 ubiquitination upregulated the expression of MET, CCND1 and TWIST1. In clinical HCC samples, TRIB3 expression was correlated with MET and FOXO1 levels. Liver-specific knockdown of TRIB3 by AAV8-shTRIB3 significantly inhibited MET-driven HCC development.
Conclusions Our results revealed that TRIB3 and COP1 act as key mediators in MET-driven HCC progression. Targeting the MET-TRIB3-FOXO1 regulatory axis may offer a promising therapeutic strategy to counteract oncogenic signaling and impede HCC advancement.
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Correspondence to Editorial 1 on “MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation” Tiantian Wang, Wenjie Huang, Limin Xia Clinical and Molecular Hepatology.2026; 32(1): e90. CrossRef
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