RESUMO
BACKGROUND AND AIMS: Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. APPROACH AND RESULTS: A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. CONCLUSIONS: In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO.
Assuntos
Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Animais , Carbamoil-Fosfato Sintase (Amônia)/deficiência , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Metilação de DNA , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Transcriptoma , Distúrbios Congênitos do Ciclo da Ureia/enzimologia , Distúrbios Congênitos do Ciclo da Ureia/genética , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/patologiaRESUMO
BACKGROUND: There is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. METHODS: Cross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. RESULTS: Data for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported. The majority of patients (70%; n=327) were aged 0-16y and 30% (n=137) >16y. Prescribed median protein intake/kg body weight decreased with age with little variation between disorders. The UK tended to give more total protein than other European countries particularly in infancy. Supplements of essential amino acids (EAA) were prescribed for 38% [n=174] of the patients overall, but were given more commonly in arginase deficiency (74%), CPS (48%) and citrullinaemia (46%). Patients in Germany (64%), Portugal (67%) and Sweden (100%) were the most frequent users of EAA. Only 18% [n=84] of patients were prescribed tube feeds, most commonly for CPS (41%); and 21% [n=97] were prescribed oral energy supplements. CONCLUSIONS: Dietary treatment for UCD varies significantly between different conditions, and between and within European IMD centres. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are required.
Assuntos
Aminoácidos Essenciais/metabolismo , Dieta com Restrição de Proteínas , Distúrbios Congênitos do Ciclo da Ureia/dietoterapia , Distúrbios Congênitos do Ciclo da Ureia/patologia , Adolescente , Adulto , Aminoácido N-Acetiltransferase/deficiência , Arginase/metabolismo , Acidúria Argininossuccínica/dietoterapia , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/deficiência , Criança , Pré-Escolar , Citrulinemia/dietoterapia , Europa (Continente) , Humanos , Lactente , Recém-Nascido , Ornitina Carbamoiltransferase/metabolismo , Inquéritos e Questionários , Resultado do Tratamento , Distúrbios Congênitos do Ciclo da Ureia/enzimologiaRESUMO
Because creatine and creatine phosphate are irreversibly converted to creatinine, there is a continuous need for their replacement. This occurs by means of diet and de novo synthesis. Dietary creatine is provided in animal products and can amount to about half of the required amount. Synthesis provides the remainder. Creatine synthesis is a major component of arginine metabolism, amounting to more than 20% of the dietary intake of this amino acid. Creatine metabolism is of importance to patients with urea cycle disorders in two ways, both related to arginine levels. In patients with arginase deficiency, markedly elevated arginine levels may result in higher concentrations of guanidinoacetate and higher rates of creatine synthesis. This is of concern because it is thought that elevated levels of guanidinoacetate may exert neurotoxic effects. In the case of the other urea cycle disorders, arginine levels are markedly decreased unless the patients are supplemented with this amino acid. Decreased levels of arginine may result in decreased rates of creatine synthesis. This may be compounded by the fact that such patients, maintained on low protein diets, will also have lower dietary creatine intakes. There is some evidence that this may decrease brain creatine levels which may contribute to the neurological symptoms exhibited by these patients. It is clear that patients with urea cycle disorders also have altered creatine metabolism. Whether this contributes in a significant way to their neurological symptoms remains an open question.