Abstract
Activated mTORC2/AKT signaling plays a role in hepatocellular carcinoma (HCC). Research has shown that TSC/mTORC1 and FOXO1 are distinct downstream effectors of AKT signaling in liver regeneration and metabolism. However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood. Amplification and activation of c-MYC are key molecular events in HCC. In this study, we explored the roles of tuberous sclerosis complex/mTORC1 (TSC/mTORC1) and FOXO1 as downstream effectors of mTORC2/AKT1 in c-MYC-induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had a minimal effect on c-MYC-induced HCC. In contrast, loss of mTORC2 inhibited c-MYC-induced HCC, an effect that was completely reversed by ablation of TSC2, which activated mTORC1. Additionally, we discovered that p70/RPS6 and 4EBP1/eIF4E acted downstream of mTORC1, regulating distinct molecular pathways. Notably, the 4EBP1/eIF4E cascade is crucial for cell proliferation and glycolysis in c-MYC-induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2/mTORC1 pathway in c-MYC-driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC-dependent HCC formation. Our findings demonstrate that the TSC/mTORC1/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC-driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC-driven HCC.
Keywords:
Hepatology; Liver cancer; Mouse models; Oncology; Signal transduction.
MeSH terms
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Animals
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Carcinoma, Hepatocellular* / genetics
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Carcinoma, Hepatocellular* / metabolism
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Carcinoma, Hepatocellular* / pathology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism
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Forkhead Box Protein O1 / genetics
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Forkhead Box Protein O1 / metabolism
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Liver Neoplasms, Experimental / genetics
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Liver Neoplasms, Experimental / metabolism
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Liver Neoplasms, Experimental / pathology
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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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Mechanistic Target of Rapamycin Complex 2* / genetics
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Mechanistic Target of Rapamycin Complex 2* / metabolism
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Mice
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Mice, Knockout
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Proto-Oncogene Proteins c-akt* / genetics
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Proto-Oncogene Proteins c-akt* / metabolism
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Proto-Oncogene Proteins c-myc* / genetics
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Proto-Oncogene Proteins c-myc* / metabolism
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Signal Transduction*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Tuberous Sclerosis Complex 2 Protein* / genetics
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Tuberous Sclerosis Complex 2 Protein* / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-myc
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Tuberous Sclerosis Complex 2 Protein
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Mechanistic Target of Rapamycin Complex 2
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Tsc2 protein, mouse
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Akt1 protein, mouse
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Myc protein, mouse
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Multiprotein Complexes
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Chromosomal Proteins, Non-Histone
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Foxo1 protein, mouse
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Tumor Suppressor Proteins
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Forkhead Box Protein O1
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TOR Serine-Threonine Kinases
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Cell Cycle Proteins