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Multi-omics analysis of liver molecular dysregulation leading to non-viral related hepatocellular carcinoma development

ABSTRACT: Chronic liver diseases exhibit diverse backgrounds, and it is believed that numerous factors contribute to progression to cancer. To achieve effective prevention of non-viral hepatocellular carcinoma, it is imperative to identify fundamental molecular abnormalities at the patient level. Utilizing cancer-adjacent liver tissues obtained from hepatocellular carcinoma patients (chronic liver disease), we conducted RNA-Seq and metabolome analyses. In the chronic liver disease cohort, upregulation of inflammation-associated signals was observed, concomitant with accumulation of acylcarnitine and fatty acid and depletion of NADP+, gamma-tocopherol, and dehydroisoandrosterone-3-sulfate-1 (DHEAS). To minimize heterogeneity, we performed multi-omics clustering, successfully categorizing the chronic liver disease cases into two distinct subtypes. Subtype 1 demonstrated elevated inflammatory levels, whereas Subtype 2 included a disproportionately high proportion of elderly cases. Furthermore, RNA-Seq analysis revealed upregulation of inflammatory signals in Subtype 1, while both subtypes exhibited downregulation of fatty acid metabolism. Metabolome analysis indicated a tendency of increased acylcarnitine levels in Subtype 1 and augmented fatty acid accumulation in Subtype 2. Validation of differentially expressed genes using the Gene Expression Omnibus (GEO) dataset revealed the potential for amelioration through supplementation with antioxidants such as epigallocatechin gallate (ECGC).

ORGANISM(S): Homo sapiens

PROVIDER: GSE244826 | GEO | 2025/03/02

REPOSITORIES: GEO

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Project description:How hepatocytes respond to a fatty acid stimulus is the topic of continuous research, since it is essential for our understanding of non-alcoholic fatty liver disease a pathology with a hard to detect onset, estimated to be present in a quarter of the adult human population. As advanced stages include cirrhosis and development of hepatocellular carcinoma, early detection and intervention is crucial. To improve our understanding of the development of non-alcoholic fatty liver disease we treated a human hepatoma cell line model, HepG2, with increasing concentrations of common fatty acids namely myristic, palmitic and oleic acid. To reproduce more representative conditions, we also included combinations of these fatty acids and monitored the cellular response with an in-depth proteomics approach and imaging techniques. The two saturated fatty acids presented a similar phenotype of a dose dependent decrease of proliferation rates and little lipid droplet formation. Interestingly, our data corroborated that this drop in proliferation rates was due to delayed cell cycle progression following myristic acid treatment, whereas palmitic acid led to cellular apoptosis. In contrast, oleic acid, as well as saturated fatty acid mixtures with oleic acid, led to a dose dependent increase of lipid droplet volume without the adverse impact on proliferation. Comparing the outcomes from harmful single fatty acid treatments and the well tolerated fatty acid mixes, we were able to differentiate between fatty acid specific cellular responses and likely common lipotoxic denominators. Two of them, A2M and SERPINA3, are modulators of the innate immune system and are likely involved in the inflammation occurring on systemic level. The remaining four include transcription factors like H2AFY, which recently has been proposed as a biomarker for hepatocellular carcinoma. Conclusively, our study not only manages to contextualise proteome alterations following fatty acid treatment, but also highlights differences between cellular effects of two common saturated fatty acids.

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Multi-omics analysis of liver molecular dysregulation leading to non-viral related hepatocellular carcinoma development

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