title: Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis.
abstract: Metabolic changes are associated with cancer, but whether they are just bystander effects of deregulated oncogenic signaling pathways or characterize early phases of tumorigenesis remains unclear. Here we show in a rat model of hepatocarcinogenesis that early preneoplastic foci and nodules that progress towards hepatocellular carcinoma (HCC) are characterized both by inhibition of oxidative phosphorylation (OXPHOS) and by enhanced glucose utilization to fuel the pentose phosphate pathway (PPP). These changes respectively require increased expression of the mitochondrial chaperone TRAP1 and of the transcription factor NRF2 that induces the expression of the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase (G6PD), following miR-1 inhibition. Such metabolic rewiring exclusively identifies a subset of aggressive cytokeratin-19 positive preneoplastic hepatocytes and not slowly growing lesions. No such metabolic changes were observed during non-neoplastic liver regeneration occurring after two/third partial hepatectomy. TRAP1 silencing inhibited the colony forming ability of HCC cells while NRF2 silencing decreased G6PD expression and concomitantly increased miR-1; conversely, transfection with miR-1 mimic abolished G6PD expression. Finally, in human HCC patients increased G6PD expression levels correlates with grading, metastasis and poor prognosis. Our results demonstrate that the metabolic deregulation orchestrated by TRAP1 and NRF2 is an early event restricted to the more aggressive preneoplastic lesions.
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, 09124, Cagliari, Italy.
authors.forename: Marta Anna
authors.initials: MA
authors.lastname: Kowalik
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35122, Padova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Guzzo
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firenze and Tuscan Tumor Institute, 50134, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morandi
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, 09124, Cagliari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Perra
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Menegon
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35122, Padova, Italy.
authors.forename: Ionica
authors.initials: I
authors.lastname: Masgras
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35122, Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Trevisan
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, 09124, Cagliari, Italy.
authors.forename: Maria Maddalena
authors.initials: MM
authors.lastname: Angioni
authors.affiliation: Azienda Ospedaliero-Universitaria Policlinico S. Orsola Malpighi, 40138, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fornari
authors.affiliation: Molecular Pathology Division, Institute of Pathology, University Hospital of Basel, CH-4003, Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, 09124, Cagliari, Italy.
authors.forename: Giovanna Maria
authors.initials: GM
authors.lastname: Ledda-Columbano
authors.affiliation: Azienda Ospedaliero-Universitaria Policlinico S. Orsola Malpighi, 40138, Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gramantieri
authors.affiliation: Molecular Pathology Division, Institute of Pathology, University Hospital of Basel, CH-4003, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firenze and Tuscan Tumor Institute, 50134, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35122, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rasola
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, 09124, Cagliari, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D065150:Cellular Reprogramming / Q000187:drug effects; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D060787:Neoplasm Grading; D010085:Oxidative Phosphorylation; D010427:Pentose Phosphate Pathway; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D011916:Rats, Inbred F344; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018841:HSP90 Heat-Shock Proteins; D053539:Keratin-19; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C092306:TRAP1 protein, human; C549284:TRAP1 protein, rat; D005954:Glucosephosphate Dehydrogenase
keywords: HCC; NRF2; TRAP1; oxidative phosphorylation; pentose phosphate pathway