Mannose-Binding Lectin 2 as a Potential Therapeutic Target for Hepatocellular Carcinoma: Multi-Omics Analysis and Experimental Validation

SIMPLE SUMMARY: This study focuses on understanding the role of mannose-binding lectin 2 (MBL2) in hepatocellular carcinoma (HCC) and its potential as a target for therapy. Our objective was to investigate the influence of MBL2 on the proliferation and metastasis of hepatocellular carcinoma using integrated multi-omics analysis and experimental validation, with a specific emphasis on MBL2-related microRNAs. The results showed that low levels of MBL2 were associated with poor prognosis in HCC patients. We also found that increasing MBL2 levels could directly inhibit HCC cell growth and spread. Furthermore, miR-34c-3p was found to be a regulator of MBL2 expression. These findings provide new insights into the development of HCC and suggest that increasing MBL2 levels could be a potential strategy for HCC treatment. ABSTRACT: Mannose-binding lectin 2 (MBL2), a member of the multimeric lectin family, is crucial in immune regulation and tumor development. MBL2 gene polymorphisms are associated with the risk and prognosis of various tumors, including hepatocellular carcinoma (HCC). Its functional role in HCC remains largely unclear. In this study, we aimed to identify whether MBL2 is a key regulator and a potential therapeutic target for HCC. A bioinformatics analysis revealed close relationships among MBL2 downregulation, the tumor-associated proliferation and metastasis pathway, and tumor immunosuppressive microenvironments. Lower expression of MBL2 in HCC patients was linked to an unfavorable prognosis. A cell counting kit-8 assay, colony formation assay, transwell migration assay, and wound healing assay further confirmed that the overexpression of MBL2 could directly inhibit the proliferation and metastasis of HCC. Moreover, MBL2 expression was regulated by miR-34c-3p, as confirmed by the dual-luciferase reporter assay, thereby demonstrating tumor progression in HCC cells. Thus, our study offers the first comprehensive confirmation of the role of MBL2 in the development of HCC through multi-omics analysis and experimental validation. Furthermore, miR-34c-3p was found to be an upstream mechanism of the downregulation of MBL2 expression and could be a promising therapeutic target, expanding treatment options for patients with HCC.