The Prognostic and Drug-targeting Value of Lymphoid Enhancer-binding Factor-1 in Hepatocellular Carcinoma

Abstract

Background: Lymphoid Enhancer-Binding Factor-1 (LEF1) was previously reported to contribute to a variety of malignancies, including Hepatocellular Carcinoma (HCC). However, its role in HCC is poorly understood.

Objectives: To explore the role of LEF1 in HCC, including its prognostic and drug-targeting value.

Methods: The LEF1 expression and patient characteristics were investigated. The associations between clinical characteristics and LEF1 were analyzed using both univariate and multivariate logistic regression. Cox regression and Kaplan-Meier curves were used to explore the clinicopathological factors related to overall survival in patients with HCC. A nomogram to predict the survival rate was constructed and validated. The Kyoto Encyclopedia of Genes and Genomes database (KEGG) was used to explore the function of LEF1. Gene Set Enrichment Analysis (GSEA) was also performed using The Cancer Genome Atlas dataset. Furthermore, compounds that may have the potential to be targeted drugs in the treatment of LEF1-overexpressing HCC were identified using the Comparative Toxicogenomics Database (CTD), patents about these drugs in HCC were also reviewed through Worldwide Espacenet® and Patentscope®.

Results: Increased expression of LEF1 was significantly associated with high histological grade of HCC (odds ratio (OR) = 2.521 for grade (G) 2 vs. G1, OR = 2.550 for G3 vs. G1, OR = 7.081 for G4 vs. G1, all P < 0.05). A Kaplan-Meier survival curve showed that HCC patients with LEF1 overexpression had a poor prognosis compared with those with normal LEF1 expression (P = 0.025). Multivariate Cox regression analysis revealed that LEF1 is an independent prognostic factor for the overall survival of patients with HCC (Hazard Ratio (HR) = 1.095; P = 0.04). The constructed nomogram to predict the survival rate produced a statistically significant prediction (area under the curve (AUC) = 86.68). In addition, Gene Ontology (GO) and KEGG analysis of genes co-expressed with the protein showed that LEF1 was associated with transcriptional regulation. GSEA suggested that the cell cycle, the WNT signaling pathway, and the NOTCH signaling pathway may be the key pathways regulated by LEF1 in HCC. Furthermore, the Comparative Toxicogenomics Database (CTD) identified nine compounds that may have the potential to be targeted drugs in the treatment of LEF1-overexpressing HCC. Patent reviews suggested that these drugs may show some efficacy in HCC, but whether these drugs interact with LEF1 and improve the prognosis for patients with HCC remains to be explored.

Conclusion: LEF1 is a latent prognostic molecular biomarker of HCC. The cell cycle, and WNT and NOTCH signaling pathways are regulated by LEF1 in HCC. LEF1 could be a potential drug target for HCC.

Keywords: Hepatocellular carcinoma; LEF1; NOTCH; WNT; drug target.; oncogene; prognostic biomarker.