MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation
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 ME...
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Korean Association for the Study of the Liver
2025-07-01
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| Series: | Clinical and Molecular Hepatology |
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| Online Access: | http://e-cmh.org/upload/pdf/cmh-2024-1163.pdf |
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| author | Tiantian Wang Dean Rao Chenan Fu Zhoubin Sun Yiming Luo Junli Lu Jie Jin Han Li Feimu Fan Huifang Liang Wenjie Huang Limin Xia |
| author_facet | Tiantian Wang Dean Rao Chenan Fu Zhoubin Sun Yiming Luo Junli Lu Jie Jin Han Li Feimu Fan Huifang Liang Wenjie Huang Limin Xia |
| author_sort | Tiantian Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-552e1aa29b4e443482174c4a778224e9 |
| institution | Kabale University |
| issn | 2287-2728 2287-285X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Korean Association for the Study of the Liver |
| record_format | Article |
| series | Clinical and Molecular Hepatology |
| spelling | doaj-art-552e1aa29b4e443482174c4a778224e92025-08-20T03:50:06ZengKorean Association for the Study of the LiverClinical and Molecular Hepatology2287-27282287-285X2025-07-013131032105710.3350/cmh.2024.11632234MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradationTiantian Wang0Dean Rao1Chenan Fu2Zhoubin Sun3Yiming Luo4Junli Lu5Jie Jin6Han Li7Feimu Fan8Huifang Liang9Wenjie Huang10Limin Xia11 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaBackground/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.http://e-cmh.org/upload/pdf/cmh-2024-1163.pdfhepatocellular carcinomamettrib3cop1foxo1 |
| spellingShingle | Tiantian Wang Dean Rao Chenan Fu Zhoubin Sun Yiming Luo Junli Lu Jie Jin Han Li Feimu Fan Huifang Liang Wenjie Huang Limin Xia MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation Clinical and Molecular Hepatology hepatocellular carcinoma met trib3 cop1 foxo1 |
| title | MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation |
| title_full | MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation |
| title_fullStr | MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation |
| title_full_unstemmed | MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation |
| title_short | MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation |
| title_sort | met promotes hepatocellular carcinoma development through the promotion of trib3 mediated foxo1 degradation |
| topic | hepatocellular carcinoma met trib3 cop1 foxo1 |
| url | http://e-cmh.org/upload/pdf/cmh-2024-1163.pdf |
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