Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma.
Cell Commun Signal
; 18(1): 97, 2020 06 23.
Article
em En
| MEDLINE
| ID: mdl-32576292
ABSTRACT
BACKGROUND:
Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Increased aerobic glycolysis supports cancer cell survival and rapid proliferation and predicts a poor prognosis in cancer patients.METHODS:
Molecular profiles from The Cancer Genome Atlas (TCGA) cohort were used to analyze the prognostic value of glycolysis gene signature in human cancers. Gain- and loss-of-function studies were performed to key drivers implicated in hepatocellular carcinoma (HCC) glycolysis. The molecular mechanisms underlying Osteopontin (OPN)-mediated glycolysis were investigated by real-time qPCR, western blotting, immunohistochemistry, luciferase reporter assay, and xenograft and diethyl-nitrosamine (DEN)-induced HCC mouse models.RESULTS:
Increased glycolysis predicts adverse clinical outcome in many types of human cancers, especially HCC. Then, we identified a handful of differentially expressed genes related to HCC glycolysis. Gain- and loss-of-function studies showed that OPN promotes, while SPP2, LECT2, SLC10A1, CYP3A4, HSD17B13, and IYD inhibit HCC cell glycolysis as revealed by glucose utilization, lactate production, and extracellular acidification ratio. These glycolysis-related genes exhibited significant tumor-promoting or tumor suppressive effect on HCC cells and these effects were glycolysis-dependent. Mechanistically, OPN enhanced HCC glycolysis by activating the αvß3-NF-κB signaling. Genetic or pharmacological blockade of OPN-αvß3 axis suppressed HCC glycolysis in xenograft tumor model and hepatocarcinogenesis induced by DEN.CONCLUSIONS:
Our findings reveal crucial determinants for controlling the Warburg metabolism in HCC cells and provide a new insight into the oncogenic roles of OPN in HCC. Video Abstract.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
/
Glicólise
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Neoplasias Hepáticas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Commun Signal
Ano de publicação:
2020
Tipo de documento:
Article