Melanoma differentiation associated gene‐9/syndecan binding protein promotes hepatocellular carcinoma

Background and Aims: 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. Approach and Results: 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 with wild‐type (WT) littermates, Alb/MDA‐9 mice demonstrated significantly higher incidence of N-nitrosodiethylamine/phenobarbital‐induced HCC, with marked activation and infiltration of macrophages. RNA sequencing (RNA‐seq) in naive WT and Alb/MDA‐9 hepatocytes identified activation of signaling pathways associated with invasion, angiogenesis, and inflammation, especially NF‐κB and integrin‐linked kinase signaling pathways. In nonparenchymal cells purified from naive livers, single‐cell RNA‐seq showed activation of Kupffer cells and macrophages in Alb/MDA‐9 mice versus WT mice. 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. Conclusions: Alb/MDA‐9 is a mouse model with MDA‐9 overexpression in any tissue type. Our findings unravel an 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.