Abstract
Tripartite motif (TRIM) 31 is a member of the tripartite motif-containing protein family, and TRIM family proteins are involved in a broad range of biological and pathological processes. However, the role of TRIM31 in hepatocellular carcinoma (HCC) progression is not known. Here we demonstrated that TRIM31 expression was significantly upregulated in liver cancer tissues compared with paired distal non-cancerous liver tissues from HCC patients, and its overexpression was significantly correlated with advanced disease status. Both gain and loss of function assay verified that TRIM31 promoted the malignant behaviors of HCC cells through overactivation of mammalian target of rapamycin complex1 (mTORC1) pathway. We further demonstrated that TRIM31 exerted its oncogenic effect by directly interacting with the tuberous sclerosis complex (TSC) 1 and TSC2 complex, the upstream suppressor of mTORC1 pathway, and promoting the E3 ligase-mediated K48-linked ubiquitination and degradation of this complex. In conclusion, this study demonstrated TRIM31 could promote HCC progression by targeting TSC1-TSC2 complex for degradation and further overactivating mTORC1 pathway. Thus, it revealed a novel molecular mechanism of HCC progression and indicated a potential therapeutic strategy against HCC by targeting TRIM31.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / pathology*
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Carcinoma, Hepatocellular / surgery
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Cell Line, Tumor
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Cohort Studies
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Disease Progression
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Liver / pathology
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Liver / surgery
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Liver Neoplasms / genetics
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Liver Neoplasms / pathology*
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Liver Neoplasms / surgery
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Male
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Mechanistic Target of Rapamycin Complex 1 / genetics
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Mechanistic Target of Rapamycin Complex 1 / metabolism
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Mice, Inbred BALB C
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Mice, Nude
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Middle Aged
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Mutagenesis, Site-Directed
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Proteolysis
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RNA, Small Interfering / metabolism
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Signal Transduction / genetics
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Transcriptional Activation / genetics
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Tripartite Motif Proteins / genetics
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Tripartite Motif Proteins / metabolism*
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination / genetics
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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RNA, Small Interfering
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TSC1 protein, human
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TSC2 protein, human
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Tripartite Motif Proteins
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Tsc1 protein, mouse
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Tsc2 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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TRIM31 protein, human
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Ubiquitin-Protein Ligases
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Mechanistic Target of Rapamycin Complex 1