MTDH Promotes Cancer Stem Cell Phenotypes and Correlated with Immune Infiltration in Hepatocellular Carcinoma

Abstract Purpose MTDH (Metadherin) has been suggested as one of the key oncogenes in most cancer types, including hepatocellular carcinoma. The aim of this study was to investigate the role of MTDH in hepatocellular carcinoma on stemness and immune infiltration. Methods MTDH expression in HCC tissues was detected using TCGA and GEO databases. Immunohistochemistry was used to analyze tissue samples. MTDH was stably knocked down or overexpressed by transfection with lentivirus in two HCC cell lines. Invasive and migratory abilities were evaluated using matrigel invasion and wound healing assays.Western blotting and qRT-PCR were used to determine gene expression. Flow cytometry, immunofluorescence, and tumor sphere formation assays were used to identify stem-like cell characterization. MTDH inhibition was evaluated in vivo for its effects on tumor growth. The correlation of MTDH with immune cells, immunomodulators, and chemokines was analyzed through the ssGSEA and TISIDB databases. Results The expression of MTDH is increased in hepatocellular carcinoma and leads to poor prognosis. HCC cells overexpressing MTDH invaded and migrated more, exhibited a stem cell-like phenotype, and formed spheres. MTDH inhibition attenuated these effects. In vivo, inhibition of MTDH suppressed HCC progression and expression of CD133. MTDH was positively correlated with immature dendritic cells, Th2 cells, central memory CD8 T cell, memory B cell, and CXCL2. MTDH was negatively associated with activated CD8 T cell, eosinophil, activated B cell, monocyte, CX3CL1, and CXCL12. Conclusions High levels of MTDH expression in HCC patients are associated with poor prognosis, promoting tumour stemness, immune infiltration and HCC progression.