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Identification of Key Genes and Pathways in Lenvatinib-resistant Hepatocellular Carcinoma using Bioinformatic
Ming Yang1, Zhaoyue Wang1, Riga Su1
1Hepato-Pancreato-Biliary Center, School of Clinical Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218, China.
Background:
Resistance to lenvatinib poses a serious threat to the therapy of patients with Hepatocellular Carcinoma (HCC). The mechanism by which HCC develops resistance to lenvatinib is currently unknown.
Objective:
The aim of this study was to identify key genes and pathways involved in lenvatinib resistance in HCC using bioinformatic analysis and experimental validation.
Methods:
Differentially expressed genes (DEGs) were identified from the GSE186191 gene expression profile, comparing HCC cell lines with lenvatinib-resistant HCC cell lines. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were then carried out using DAVID. A protein-protein interaction network was constructed to visualize DEGs and identify hub genes. The expression and prognostic significance of these hub genes were further examined. Additionally, genomic enrichment analysis (GSEA) was utilized to investigate the potential functions of key genes. Following this, the presence of AHSG was validated in both the original Huh7 cells and the lenvatinib-resistant Huh7 (Huh7LR) cells resistant to lenvatinib through the utilization of quantitative real-time PCR (qRT-PCR).
Results:
A total of 232 DEGs were identified between HCC cell lines and those that are resistant to lenvatinib. These DEGs were significantly associated with arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, dilated cardiomyopathy, and mucin-type O-glycan biosynthesis. Three hub genes, including AHSG, C6, and ORM1, were identified. The low expression of AHSG showed a poorer prognosis in HCC. GSEA demonstrated a significant correlation between low AHSG expression and pathways involving fatty acid metabolism, ribosome function, glycine, serine, and threonine metabolism, peroxisome activity, and bile acid biosynthesis. The expression of AHSG was notably reduced in Huh7LR cells (p = 0.006) compared to Huh7 cells.
Conclusion:
Diminished AHSG expression is strongly associated with lenvatinib resistance in HCC, suggesting that it may have implications for developing effective strategies to overcome this resistance.
Insights
Reduced alpha-2-HS-glycoprotein (AHSG) expression is linked to lenvatinib resistance in hepatocellular carcinoma (HCC). This finding may help develop strategies to overcome treatment resistance in HCC patients.
Area of Science:
- Oncology
- Genomics
- Bioinformatics
Background:
- Lenvatinib resistance is a significant challenge in Hepatocellular Carcinoma (HCC) therapy.
- The underlying mechanisms of lenvatinib resistance in HCC remain largely unknown.
Purpose of the Study:
- To identify key genes and pathways implicated in lenvatinib resistance in HCC.
- To validate potential therapeutic targets through bioinformatic analysis and experimental methods.
Main Methods:
- Differential gene expression analysis of HCC cell lines versus lenvatinib-resistant HCC cell lines.
- Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis (GSEA) for pathway identification.
- Protein-protein interaction network construction to identify hub genes, including alpha-2-HS-glycoprotein (AHSG), and quantitative real-time PCR (qRT-PCR) for validation.
Main Results:
- 232 differentially expressed genes (DEGs) were identified, associated with cardiomyopathy and O-glycan biosynthesis.
- Three hub genes (AHSG, C6, ORM1) were identified; low AHSG expression correlated with poorer HCC prognosis.
- GSEA revealed associations between low AHSG expression and metabolic and ribosomal pathways; AHSG was significantly reduced in resistant cells.
Conclusions:
- Diminished alpha-2-HS-glycoprotein (AHSG) expression is a key factor associated with lenvatinib resistance in Hepatocellular Carcinoma (HCC).
- Targeting AHSG may offer a novel strategy to overcome lenvatinib resistance in HCC treatment.
