TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

Todisco, Simona; Convertini, Paolo; Iacobazzi, Vito; Infantino, Vittoria

doi:10.3390/cancers12010068

Cited by 69 publications

(64 citation statements)

References 165 publications

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“…Early studies suggested that cancer cells bypass the TCA cycle and use aerobic glycolysis, but emerging evidence suggests that some cancer cells, particularly those with the maladjusted expression of oncogenes and tumor suppressors, rely heavily on the TCA cycle to produce energy and synthesize large molecules [ 35 ]. In a variety of cancers, including HCC, the expression or activity levels of the TCA cycle and related enzymes are generally dysregulated, which is a pivotal driver of cancer development and progression [ 36 , 37 ]. In addition, wild-type P53 also has an important effect on metabolism, the mutation of P53 will lead to the enhancement of glycolysis and the reduction of oxidative phosphorylation in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

2020

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Background The E2F family of transcription factor 2 (E2F2) plays an important role in the development and progression of various tumors, but its association with hepatocellular carcinoma (HCC) remains unknown. Our study aimed to investigate the role and clinical significance of E2F2 in HCC. Methods HCC raw data were extracted from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test, Kruskal-Wallis test and logistic regression were applied to analyze the relationship between the expression of E2F2 and clinicopathologic characteristics. Cox regression and Kaplan-Meier were employed to evaluate the correlation between clinicopathologic features and survival. The biological function of E2F2 was annotated by Gene Set Enrichment Analysis (GSEA). Results The expression of E2F2 was increased in HCC samples. The expression of elevated E2F2 in HCC samples was prominently correlated with histologic grade (OR = 2.62 for G3–4 vs. G1–2, p = 1.80E-05), clinical stage (OR = 1.74 for III-IV vs. I-II, p = 0.03), T (OR = 1.64 for T3–4 vs.T1–2, p = 0.04), tumor status (OR = 1.88 for with tumor vs. tumor free, p = 3.79E-03), plasma alpha fetoprotein (AFP) value (OR = 3.18 for AFP ≥ 400 vs AFP<20, p = 2.16E-04; OR = 2.50 for 20 ≤ AFP<400 vs AFP<20, p = 2.56E-03). Increased E2F2 had an unfavorable OS (p = 7.468e− 05), PFI (p = 3.183e− 05), DFI (p = 0.001), DSS (p = 4.172e− 05). Elevated E2F2 was independently bound up with OS (p = 0.004, hazard ratio [HR] = 2.4 (95% CI [1.3–4.2])), DFI (P = 0.029, hazard ratio [HR] = 2.0 (95% CI [1.1–3.7])) and PFI (P = 0.005, hazard ratio [HR] = 2.2 (95% CI [1.3–3.9])). GSEA disclosed that cell circle, RNA degradation, pyrimidine metabolism, base excision repair, aminoacyl tRNA biosynthesis, DNA replication, p53 signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, citrate cycle TCA cycle were notably enriched in E2F2 high expression phenotype. Conclusions Elevated E2F2 can be a promising independent prognostic biomarker and therapeutic target for HCC. Additionally, cell cycle, pyrimidine metabolism, DNA replication, p53 signaling pathway, ubiquitin-mediated proteolysis, the citrate cycle TCA cycle may be the key pathway by which E2F2 participates in the initial and progression of HCC.

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Section: Discussionmentioning

confidence: 99%

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

2020

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“…Moreover, liposomal HCA, by targeting immunometabolism through ACLY metabolic enzyme, could represent an innovative approach to many pathological conditions, since inflammation underlies countless diseases. Finally, as ACLY is also overexpressed in a wide variety of tumors, such as hepatocellular carcinoma [ 2 ], it is reasonable to suppose that liposomal HCA might be useful for the treatment of cancer, maybe in combination with other drugs.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, it has been discovered that metabolic shifts of activated macrophages, in many cases shared with cancer cells [ 2 ], also involve the Krebs cycle rewiring, leading to the accumulation of citrate, succinate, and fumarate [ 3 ]. In LPS- or TNFα/IFNγ-activated macrophages, the mitochondrial citrate carrier (CIC) exports citrate from the mitochondria to the cytosol where the ATP citrate lyase (ACLY) enzyme catalyzes its conversion into oxaloacetate (OAA) and acetyl-CoA.…”

Section: Introductionmentioning

confidence: 99%

Liposome-Mediated Inhibition of Inflammation by Hydroxycitrate

et al. 2020

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Hydroxycitrate (HCA), a main organic acid component of the fruit rind of Garcinia cambogia, is a natural citrate analog that can inhibit the ATP citrate lyase (ACLY) enzyme with a consequent reduction of inflammatory mediators (i.e., nitric oxide (NO), reactive oxygen species (ROS), and prostaglandin E2 (PGE2)) levels. Therefore, HCA has been proposed as a novel means to prevent, treat, and ameliorate conditions involving inflammation. However, HCA presents a low membrane permeability, and a large quantity is required to have a biological effect. To overcome this problem, HCA was formulated in liposomes in this work, and the enhancement of HCA cell availability along with the reduction in the amount required to downregulate NO, ROS, and PGE2 in macrophages were assessed. The liposomes were small in size (~60 nm), monodispersed, negatively charged (−50 mV), and stable on storage. The in vitro results showed that the liposomal encapsulation increased by approximately 4 times the intracellular accumulation of HCA in macrophages, and reduced by 10 times the amount of HCA required to abolish LPS-induced NO, ROS, and PGE2 increase. This suggests that liposomal HCA can be exploited to target the citrate pathway involved in inflammatory processes.

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“…Early studies suggested that cancer cells bypass the TCA cycle and use aerobic glycolysis, but emerging evidence suggests that some cancer cells, particularly those with maladjusted expression of oncogenes and tumor suppressors, rely heavily on the TCA cycle to produce energy and synthesize large molecules (30). In a variety of cancers, including HCC, the expression or activity levels of the TCA cycle and related enzymes are generally dysregulated, which is a pivotal driver of cancer development and progression (31,32). In addition, wild-type P53 alos has an important effect on metabolism,the mutation of P53 will lead to the enhancement of glycolysis and the reduction of oxidative phosphorylation in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

Zeng

Cao

Tang³

2020

Preprint

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Background E2F transcription factor 2(E2F2) plays an important role in the development and progression of various tumors, but its association with hepatocellular carcinoma remains unknown.The aim of our study was to investigate the role and clinical significance of E2F2 in hepatocellular carcinoma (HCC). Methods HCC raw data were extracted from TCGA. Wilcoxon signed-rank test, Kruskal-Wallis test and logistic regression was applied to analyze the the relationship between the expression of E2F2 and clinicalpathologic charateristics. Cox regression and Kaplan-Meier was employed to evaluate the correlation between clinicopathologic features and survial. The biological function of E2F2 was annotated by Gene set enrichment analysis (GSEA). Results The expression of E2F2 was increased in HCC samples. The expression of elevated E2F2 in HCC samples was prominentlly correlated with tumor grade (OR =2.62 for G3-4 vs. G1-2, p=1.80E-05), tumor stage (OR =1.74 for III-IV vs. I-II, p=0.03), topography (OR =1.64 for T3-4 vs.T1-2, p=0.04), tumor status (OR =1.88 for with tumor vs. tumor free, p= 3.79E-03), plasma AFP value (OR =3.18 for AFP≥400 vs AFP<20, p= 2.16E-04; OR=2.50 for 20≤AFP<400 vs AFP<20, p=2.56E-03). Increased E2F2 had a unfavorable OS (p=7.468e−05), PFI (p=3.183e−05), DFI (p=0.001), DSS (p=4.172e−05). Elevated E2F2 was independently bound up with OS (p = 4.4E-04, HR = 2.4 (95% CI [1.5-3.8])) and DSS (p = 7.6E-04, HR = 3.0, (95% CI [1.6-5.6])). GSEA disclosed that cell circle, RNA degradation, pyrimidine metabolism, base excision repair, aminoacyl tRNA biosynthesis, DNA replication, p53 signalling pathway, nucleotide excision repair, ubiquitin mediated proteolysis, citrate cycle TCA cycle were notably enriched in E2F2 high expression phenotype. Conclusions Elevated E2F2 can be a promissing independent prognostic biomarker and therapeutic target for HCC. Additionally, cell cycle, pyrimidine metabolism, DNA replication, p53 signalling pathway, ubiquitin mediated proteolysis, the citrate cycle TCA cycle may be the key pathway by which E2F2 participate in the initial and progression of HCC.

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TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

Cited by 69 publications

References 165 publications

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

Liposome-Mediated Inhibition of Inflammation by Hydroxycitrate

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

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