Relationship between retinol metabolism and hepatocellular carcinoma: a comprehensive analysis of Mendelian randomization, prognostic characteristic and experiment

Abstract

Abstract Purpose Retinol metabolism is intricately linked to the occurrence and progression of hepatocellular carcinoma (HCC); however, the precise pathogenic relationship between them remains elusive. The aim of this study was to elucidate the characteristics of retinol metabolism in HCC through Mendelian randomization, prognostic model and experimental validation. Methods We used transcriptomic data related to HCC in TCGA and GEO databases for a variety of machine learning, including differential gene expression analysis, functional enrichment analysis, protein–protein network interaction, ceRNA regulatory network, and single-cell sequencing analysis. Mendelian randomization analysis was used to elucidate the causal analysis of retinol metabolism and the occurrence of HCC. Consensus cluster analysis was performed based on 11 retinol metabolism-related genes, and the prognostic model was constructed by Lasso regression and Cox regression analysis. The expression level of RDH16 gene was detected in cell lines and clinical samples, and finally the function of RDH16 gene and its regulatory relationship with miR- 665 were verified by in vitro cell experiments. Results Differentially expressed genes were mainly concentrated in the retinol metabolic pathway. Mendelian randomization analysis showed that decreased retinol metabolic activity was causally associated with the occurrence of HCC. RDH16 gene was significantly lower expressed in HCC, and inhibition of RDH16 gene expression could promote the proliferation, migration and invasion of HCC cells and inhibit cell apoptosis. miR- 665 is an upstream regulator of RDH16 gene, which can inhibit the expression and function of RDH16. Conclusion The decrease of retinol metabolic activity can promote the occurrence and development of HCC. Targeting retinol metabolic pathway may be a new direction for the treatment of HCC.

Keywords

• Hepatocellular carcinoma
• Retinol metabolism
• Mendelian randomization
• RDH16
• MiR- 665