Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma

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 αvβ3-NF-κB signaling. Genetic or pharmacological blockade of OPN-αvβ3 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.

Osteopontin Takes Center Stage in Chronic Liver Disease

“…( 61 ) A neutralizing antibody to OPN suppresses the stem‐like phenotype in HCCLM3 cells. ( 60 ) In Huh7 and HepG2 cells, OPN overexpression increases cell proliferation, ( 62 ) stem‐like properties, ( 60 ) glycolysis, ( 63 ) autophagy, and resistance to chemotherapy. ( 64 ) Conversely, SPP1 knockdown in HCCLM3 and HepG2 cells decreases proliferation, migration, and sensitivity to chemotherapy.…”

The effect of a novel glycolysis-related gene signature on progression, prognosis and immune microenvironment of renal cell carcinoma

“…However, the predictive ability of single-gene biomarkers is limited in RCC prognosis analysis and multiple-genes signature maybe a better strategy [ 16 ]. So far, only four studies have established the glycolytic risk signature in lung adenocarcinoma [ 17 ], endometrial cancer [ 16 ], hepatocellular carcinoma [ 18 ] and bladder cancer [ 19 ]. Therefore, to explore the potential roles of glycolytic metabolism and glycolysis-related genes in RCC, a series of bioinformatic analyses were performed through TCGA database (609 samples).…”

Integrated Proteomics and Bioinformatics to Identify Potential Prognostic Biomarkers in Hepatocellular Carcinoma

“… 38 Lu et al found that HSD17B13 was a tumor suppressive gene that inhibits HCC cell glycolysis as revealed by glucose utilization, lactate production, and extracellular acidification ratio. 39 PON3 is a member of Paraoxonase (PON) proteins primarily expressed in the liver, its expression and specific activities were found to negatively correlate with several inflammatory disorders and served as a prognostic predictor in HCC. 40 Song et al identified AMDHD1 was as a novel tissue-specific gene in human and mouse liver tissues.…”