Hepatology: Melanoma Differentiation Associated Gene-9/Syndecan Binding Protein (MDA-9/SDCBP) Promotes Hepatocellular Carcinoma (HCC) [Lai]

Debashri Manna,Saranya Chidambaranathan Reghupaty,Maria Del Carmen Camarena,Rachel G. Mendoza,Mark A. Subler,Jennifer E. Koblinski,Rebecca Martin,Mikhail G. Dozmorov,Nitai D. Mukhopadhyay,Jinze Liu,Xufeng Qu,Swadesh K. Das,Zhao Lai,Jolene J. Windle,Paul B. Fisher,Devanand Sarkar

Abstract

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 a 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 the NF-κB pathway blocked MDA-9-induced Spp1 induction, and knockdown 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 for using MDA-9 inhibitors as a potential treatment for aggressive HCC.

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