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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\u2013induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had a minimal effect on c-MYC\u2013induced HCC. In contrast, loss of mTORC2 inhibited c-MYC\u2013induced 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\u2013induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2\/mTORC1 pathway in c-MYC\u2013driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC\u2013dependent HCC formation. Our findings demonstrate that the TSC\/mTORC1\/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC\u2013driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC\u2013driven HCC.<\/jats:p>","DOI":"10.1172\/jci174415","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T12:00:27Z","timestamp":1727352027000},"source":"Crossref","is-referenced-by-count":19,"title":["TSC\/mTORC1 mediates mTORC2\/AKT1 signaling in c-MYC\u2013induced murine hepatocarcinogenesis via centromere protein M"],"prefix":"10.1172","volume":"134","author":[{"given":"Yi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, the First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China."},{"name":"Department of Bioengineering and Therapeutic Sciences and Liver Center, UCSF, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Oncology, Cancer Center,"},{"name":"Department of Radiation Oncology, Cancer Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoteng","family":"Qiu","sequence":"additional","affiliation":[{"name":"Division of Liver Surgery, Department of General Surgery, and"},{"name":"Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Yonemura","sequence":"additional","affiliation":[{"name":"Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences and Liver Center, UCSF, San Francisco, California, USA."},{"name":"Division of Liver Surgery, Department of General Surgery, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guofei","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences and Liver Center, UCSF, San Francisco, California, USA."},{"name":"Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences and Liver Center, UCSF, San Francisco, California, USA."},{"name":"Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Chun","sequence":"additional","affiliation":[{"name":"Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0825-3048","authenticated-orcid":true,"given":"Nianyong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Oncology, Cancer Center,"},{"name":"Department of Radiation Oncology, Cancer Center,"},{"name":"Laboratory of Single Cell Research and Liquid Biopsy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, the Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhua","family":"Song","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Laboratory for Clinical Medicine, Capital Medical University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Laboratory for Clinical Medicine, Capital Medical University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijing","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Laboratory for Clinical Medicine, Capital Medical University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youping","family":"Deng","sequence":"additional","affiliation":[{"name":"Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA."},{"name":"Department of Quantitative Health Sciences, John A. 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