CLEC4G Reverses Lenvatinib Resistance in Hepatocellular Carcinoma by Suppressing PD-1 Expression via the Wnt/β-Catenin Pathway.

Objective: The objective was to analyze the effect of C-type lectin domain family 4 member G (CLEC4G) on hepatocellular carcinoma (HCC) and investigate its impact on lenvatinib (Lenva) resistance as well as the underlying action pathway. Methods: Differentially expressed genes (DEGs) were screened from the GSE101685 dataset, followed by functional enrichment analysis. Subsequently, CLEC4G was selected for subsequent experiments. The Lenva-resistant cell line PLC/PRF/5-R was established and transfected with a CLEC4G silencing expression vector to observe alterations in its biological behavior. Sample size was estimated based on a pilot experiment (n = 3 biological replicates) with 30 clinical samples/cell experiment in each group. Additionally, the expression of the Wnt/β-catenin pathway in PLC/PRF/5-R was examined, and PLC/PRF/5-R activity after intervention with LiCl, a Wnt/β-catenin pathway activator, was evaluated. Results: A total of 51 DEGs were identified in the GSE101685 dataset. After silencing CLEC4G expression, the activities of both PLC/PRF/5 and PLC/PRF/5-R, as well as the expression of PD-1, were decreased, while apoptosis was increased (p < 0.05). Moreover, silencing CLEC4G inhibited the expression of the Wnt/β-catenin pathway (p < 0.05). After LiCl intervention, the activity of PLC/PRF/5-R was enhanced, and the expression of PD-1 was elevated (p < 0.05). Silencing CLEC4G could reverse the effect of LiCl on PLC/PRF/5-R. Conclusion: CLEC4G modulates the PD-1 expression of HCC cells through the Wnt/β-catenin pathway, thereby reversing the resistance to Lenva.