title: A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis.
abstract: Amplification and/or activation of the c-Myc proto-oncogene is one of the leading genetic events along hepatocarcinogenesis. The oncogenic potential of c-Myc has been proven experimentally by the finding that its overexpression in the mouse liver triggers tumor formation. However, the molecular mechanism whereby c-Myc exerts its oncogenic activity in the liver remains poorly understood. Here, we demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is activated and necessary for c-Myc-dependent hepatocarcinogenesis. Specifically, we found that ablation of Raptor, the unique member of mTORC1, strongly inhibits c-Myc liver tumor formation. Also, the p70 ribosomal S6 kinase/ribosomal protein S6 and eukaryotic translation initiation factor 4E-binding protein 1/eukaryotic translation initiation factor 4E signaling cascades downstream of mTORC1 are required for c-Myc-driven tumorigenesis. Intriguingly, microarray expression analysis revealed up-regulation of multiple amino acid transporters, including solute carrier family 1 member A5 (SLC1A5) and SLC7A6, leading to robust uptake of amino acids, including glutamine, into c-Myc tumor cells. Subsequent functional studies showed that amino acids are critical for activation of mTORC1 as their inhibition suppressed mTORC1 in c-Myc tumor cells. In human hepatocellular carcinoma specimens, levels of c-Myc directly correlate with those of mTORC1 activation as well as of SLC1A5 and SLC7A6.
  
  
  
  Our current study indicates that an intact mTORC1 axis is required for c-Myc-driven hepatocarcinogenesis; thus, targeting the mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of hepatocellular carcinoma with activated c-Myc signaling. (Hepatology 2017;66:167-181).
authors.affiliation: Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.|Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
authors.forename: Pin
authors.initials: P
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Ge
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.|School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.|Department of Thyroid and Breast Surgery, Jinan Military General Hospital of PLA, Jinan, Shandong, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
authors.forename: Li
authors.initials: L
authors.lastname: Che
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Sun
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Cheng
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
authors.forename: Yuedong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Pilo
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cigliano
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Giovanni M
authors.identifier: 0000-0003-3265-2823
authors.initials: GM
authors.lastname: Pes
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Pascale
authors.affiliation: Pietro Valdoni Surgery Department, University of Rome La Sapienza, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Brozzetti
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Vidili
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Porcu
authors.affiliation: Unit of Pathology, Azienda Ospedaliero Universitaria Sassari, Sassari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cossu
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palmieri
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Sini
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.
authors.forename: Junyan
authors.initials: J
authors.lastname: Tao
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.|Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.|Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Ligong
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.|School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001707:Biopsy, Needle; D063646:Carcinogenesis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D004195:Disease Models, Animal; D016259:Genes, myc; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D016016:Proportional Hazards Models; D000090063:Proto-Oncogene Mas; D011897:Random Allocation; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C000715470:MAS1 protein, human; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus