Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling
Abstract Background Ufm1-specific ligase 1 (Ufl1) and Ufm1-binding protein 1 (Ufbp1), as putative targets of ubiquitin-fold modifier 1 (Ufm1), have been implicated in several pathogenesis-related signaling pathways. However, little is known about their functional roles in liver disease. Methods Hepa...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-023-02681-6 |
| _version_ | 1797831850318626816 |
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| author | Fanghui Chen Le Sheng Tianci Zhou Li Yan Reid Loveless Honglin Li Yong Teng Yafei Cai |
| author_facet | Fanghui Chen Le Sheng Tianci Zhou Li Yan Reid Loveless Honglin Li Yong Teng Yafei Cai |
| author_sort | Fanghui Chen |
| collection | DOAJ |
| description | Abstract Background Ufm1-specific ligase 1 (Ufl1) and Ufm1-binding protein 1 (Ufbp1), as putative targets of ubiquitin-fold modifier 1 (Ufm1), have been implicated in several pathogenesis-related signaling pathways. However, little is known about their functional roles in liver disease. Methods Hepatocyte-specific Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice were used to study their role in liver injury. Fatty liver disease and liver cancer were induced by high-fat diet (HFD) and diethylnitrosamine (DEN) administration, respectively. iTRAQ analysis was employed to screen for downstream targets affected by Ufbp1 deletion. Co-immunoprecipitation was used to determine the interactions between the Ufl1/Ufbp1 complex and the mTOR/GβL complex. Results Ufl1 Δ/Δhep or Ufbp1 Δ/Δhep mice exhibited hepatocyte apoptosis and mild steatosis at 2 months of age and hepatocellular ballooning, extensive fibrosis, and steatohepatitis at 6–8 months of age. More than 50% of Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice developed spontaneous hepatocellular carcinoma (HCC) by 14 months of age. Moreover, Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice were more susceptible to HFD-induced fatty liver and DEN-induced HCC. Mechanistically, the Ufl1/Ufbp1 complex directly interacts with the mTOR/GβL complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/GβL complex and activates oncogenic mTOR signaling to drive HCC development. Conclusions These findings reveal the potential role of Ufl1 and Ufbp1 as gatekeepers to prevent liver fibrosis and subsequent steatohepatitis and HCC development by inhibiting the mTOR pathway. |
| first_indexed | 2024-04-09T13:59:24Z |
| format | Article |
| id | doaj.art-e23daf3fac0a4d4b99326cc2fc373db7 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-09T13:59:24Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-e23daf3fac0a4d4b99326cc2fc373db72023-05-07T11:27:16ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-05-0142112110.1186/s13046-023-02681-6Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signalingFanghui Chen0Le Sheng1Tianci Zhou2Li Yan3Reid Loveless4Honglin Li5Yong Teng6Yafei Cai7College of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityDepartment of Radiation Oncology, Linyi People HospitalDepartment of Oral Biology and Diagnostic Sciences, Georgia Cancer Center, Augusta UniversityDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta UniversityDepartment of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of MedicineCollege of Animal Science and Technology, Nanjing Agricultural UniversityAbstract Background Ufm1-specific ligase 1 (Ufl1) and Ufm1-binding protein 1 (Ufbp1), as putative targets of ubiquitin-fold modifier 1 (Ufm1), have been implicated in several pathogenesis-related signaling pathways. However, little is known about their functional roles in liver disease. Methods Hepatocyte-specific Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice were used to study their role in liver injury. Fatty liver disease and liver cancer were induced by high-fat diet (HFD) and diethylnitrosamine (DEN) administration, respectively. iTRAQ analysis was employed to screen for downstream targets affected by Ufbp1 deletion. Co-immunoprecipitation was used to determine the interactions between the Ufl1/Ufbp1 complex and the mTOR/GβL complex. Results Ufl1 Δ/Δhep or Ufbp1 Δ/Δhep mice exhibited hepatocyte apoptosis and mild steatosis at 2 months of age and hepatocellular ballooning, extensive fibrosis, and steatohepatitis at 6–8 months of age. More than 50% of Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice developed spontaneous hepatocellular carcinoma (HCC) by 14 months of age. Moreover, Ufl1 Δ/Δhep and Ufbp1 Δ/Δhep mice were more susceptible to HFD-induced fatty liver and DEN-induced HCC. Mechanistically, the Ufl1/Ufbp1 complex directly interacts with the mTOR/GβL complex and attenuates mTORC1 activity. Ablation of Ufl1 or Ufbp1 in hepatocytes dissociates them from the mTOR/GβL complex and activates oncogenic mTOR signaling to drive HCC development. Conclusions These findings reveal the potential role of Ufl1 and Ufbp1 as gatekeepers to prevent liver fibrosis and subsequent steatohepatitis and HCC development by inhibiting the mTOR pathway.https://doi.org/10.1186/s13046-023-02681-6Ufl1/Ufbp1mTORHepatic fibrosisFatty liverHCC |
| spellingShingle | Fanghui Chen Le Sheng Tianci Zhou Li Yan Reid Loveless Honglin Li Yong Teng Yafei Cai Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling Journal of Experimental & Clinical Cancer Research Ufl1/Ufbp1 mTOR Hepatic fibrosis Fatty liver HCC |
| title | Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling |
| title_full | Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling |
| title_fullStr | Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling |
| title_full_unstemmed | Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling |
| title_short | Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling |
| title_sort | loss of ufl1 ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mtor signaling |
| topic | Ufl1/Ufbp1 mTOR Hepatic fibrosis Fatty liver HCC |
| url | https://doi.org/10.1186/s13046-023-02681-6 |
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