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The Consumption of Cholesterol-Enriched Diets Conditions the Development of a Subtype of HCC with High Aggressiveness and Poor Prognosis.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH) result as a consequence of diverse conditions, mainly unbalanced diets. Particularly, high-fat and cholesterol content, as well as carbohydrates, such as those commonly ingested in Western countries, frequently drive adverse metabolic alterations in the liver and promote NAFLD development. Lipid liver overload is also one of the main risk factors for initiation and progression of hepatocellular carcinoma (HCC), but detailed knowledge on the relevance of high nutritional cholesterol remains elusive. We were aimed to characterize HCC development in mice fed with a Western diet (high in lipids and cholesterol) and to identify molecular alterations that define a subtype of liver cancer induced by lipid overload. Mice under western or high cholesterol diets more frequently developed tumors with a more aggressive phenotype than animals fed with a chow diet. Associated changes involved macrophage infiltration, angiogenesis, and stemness features. RNA-seq revealed a specific gene expression signature (Slc41a; Fabp5; Igdcc4 and Mthfd1l) resembling the adverse phenotypic features and poor clinical outcomes seen in patients with HCC. In conclusion; consumption of lipid enriched diets; particularly cholesterol; could accelerate HCC development with an aggressive phenotype and poor prognosis.

SUBMITTER: Simoni-Nieves A

PROVIDER: S-EPMC8038696 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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The Consumption of Cholesterol-Enriched Diets Conditions the Development of a Subtype of HCC with High Aggressiveness and Poor Prognosis.

Simoni-Nieves Arturo A Salas-Silva Soraya S Chávez-Rodríguez Lisette L Escobedo-Calvario Alejandro A Desoteux Matthis M Bucio Leticia L Souza Verónica V Miranda-Labra Roxana U RU Muñoz-Espinosa Linda E LE Coulouarn Cédric C Gutiérrez-Ruiz María Concepción MC Marquardt Jens U JU Gomez-Quiroz Luis E LE

Cancers 20210406 7

Non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH) result as a consequence of diverse conditions, mainly unbalanced diets. Particularly, high-fat and cholesterol content, as well as carbohydrates, such as those commonly ingested in Western countries, frequently drive adverse metabolic alterations in the liver and promote NAFLD development. Lipid liver overload is also one of the main risk factors for initiation and progression of hepatocellular carc ...[more]

PMID: 33917315

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Project description: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.

Dataset Information

The Consumption of Cholesterol-Enriched Diets Conditions the Development of a Subtype of HCC with High Aggressiveness and Poor Prognosis.

Publications

The Consumption of Cholesterol-Enriched Diets Conditions the Development of a Subtype of HCC with High Aggressiveness and Poor Prognosis.

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