SLC11A1 upregulation mediates the progression of hepatocellular carcinoma and decreased sensitivity to cisplatin by mediating macrophage M2 polarization.
Abstract
Background
Dysregulated expression of Solute Carrier Family 11 Member 1 (SLC11A1) has been found to be dysregulated in multiple human cancers and is implicated in tumor progression. However, the precise functions and underlying mechanisms of SLC11A1 in hepatocellular carcinoma (HCC) remains largely unknown.
Methods
Transcriptomic data from HCC patients were analyzed via bioinformatics approaches (co-expression network profiling, functional enrichment) to explore SLC11A1 expression, immune infiltration, and biological functions. Functional assays were performed to validate its roles in HCC cell proliferation, migration, invasion, and tumor growth. The effect of SLC11A1 on cisplatin sensitivity was evaluated. Immunohistochemistry (IHC) and immunofluorescence were carried out to assess tumor cell proliferation and macrophage polarization markers in tumor tissues. Western blot and rescue experiments with JAK2/STAT3 inhibitors were conducted to explore the underlying mechanism.
Results
SLC11A1 expression was altered in HCC tissues based on bioinformatics analysis, and its high expression correlated with poorer survival of patients with HCC. Functionally, SLC11A1 overexpression promoted HCC cell proliferation, migration, invasion, and tumor growth, whereas its knockdown suppressed these malignant phenotypes and enhanced cisplatin sensitivity. SLC11A1 upregulation was associated with immune cell infiltration. SLC11A1 overexpression promoted M2 polarization while inhibiting M1 polarization of macrophages, while SLC11A1 downregulation showed the opposite effects on macrophage polarization. Mechanistically, SLC11A1 upregulation promoted IL-6 and S100A9 expression, and enhanced the phosphorylation of JAK2 and STAT3. Inhibition of JAK2/STAT3 reversed the oncogenic effects of SLC11A1 upregulation. An
Conclusion
SLC11A1 upregulation is associated with enhanced malignant behaviors, reduced cisplatin sensitivity, and M2 macrophage polarization in HCC potentially through mediating the IL-6/JAK2/STAT3/S100A9 axis.