LAUSR

The oncogene Melanoma differentiation associated gene-9/syndecan binding protein (MDA-9/SDCBP) is overexpressed in many cancers promoting aggressive, metastatic disease. However, the role of MDA-9 in regulating hepatocellular carcinoma (HCC) has not been well-studied. To unravel the function of MDA-9 in HCC, we generated and characterized a transgenic mouse with hepatocyte-specific overexpression of MDA-9 (Alb/MDA-9). Compared to WT littermates, Alb/MDA-9 mice demonstrated significantly higher incidence of N-nitrosodiethylamine/phenobarbital-induced HCC, with marked activation and infiltration of macrophages. RNA-seq in naïve WT and Alb/MDA-9 hepatocytes identified activation of signaling pathways associated with invasion, angiogenesis and inflammation, especially NF-κB and integrin-linked kinase (ILK) signaling pathways. scRNA-seq in non-parenchymal cells purified from naïve livers showed activation of Kupffer cells and macrophages in Alb/MDA-9 mice vs WT. A robust increase in the expression of Secreted phosphoprotein 1 (Spp1/osteopontin) was observed upon overexpression of MDA-9. Inhibition of NF-κB pathway blocked MDA-9-induced Spp1 induction, and knock down of Spp1 resulted in inhibition of MDA-9-induced macrophage migration as well as angiogenesis. Alb/MDA-9 is the first mouse model with MDA-9 overexpression in any tissue type. Our findings unravel a novel HCC-promoting role of MDA-9 mediated by NF-κB and Spp1, and support the rationale of using MDA-9 inhibitors as a potential treatment for aggressive HCC.