Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths world-wide. Liver transplantation, surgical resection, trans-arterial chemoembolization, and radio frequency ablation are effective strategies to treat early stage HCC. Unfortunately, HCC is usually diagnosed at an advanced stage and there are not many treatment options for late stage HCC. First-line therapy for late stage HCC includes sorafenib and lenvatinib. However, these treatments provide only an approximate three month increase in survival. Besides, they cannot specifically target cancer cells that lead to a wide array of side effects. Patients on these drugs develop resistance within a few months and have to rely on second-line therapy that includes regorafenib, pembrolizumab, nivolumab, and cabometyx. These disadvantages make gene therapy approach to treat HCC an attractive option. The two important questions that researchers have been trying to answer in the last 2–3 decades are what genes should be targeted and what delivery systems should be used. The objective of this review is to analyze the changing landscape of HCC gene therapy, with a focus on these two questions.

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Obesity is an enormous global health problem, and obesity-induced nonalcoholic steatohepatitis (NASH) is contributing to a rising incidence and mortality for hepatocellular carcinoma (HCC). Increase in de novo lipogenesis and decrease in fatty acid β-oxidation (FAO) underlie hepatic lipid accumulation in NASH. Astrocyte-elevated gene-1/ metadherin (AEG-1) overexpression contributes to both NASH and HCC. AEG-1 harbors an LXXLL motif through which it blocks activation of peroxisome proliferator activated receptor α (PPARα), a key regulator of FAO. To better understand the role of LXXLL motif in mediating AEG-1 function, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology, we generated a mouse model (AEG-1-L24K/L25H) in which the LXXLL motif in AEG-1 was mutated to LXXKH. We observed increased activation of PPARα in AEG-1-L24K/L25H livers providing partial protection from high-fat diet-induced steatosis. Interestingly, even with equal gene dosage levels, compared with AEG-1-wild-type livers, AEG-1-L24K/L25H livers exhibited increase in levels of lipogenic enzymes, mitogenic activity and inflammation, which are attributes observed when AEG-1 is overexpressed. These findings indicate that while LXXLL motif favors steatotic activity of AEG-1, it keeps in check inflammatory and oncogenic functions, thus maintaining a homeostasis in AEG-1 function. AEG-1 is being increasingly appreciated as a viable target for ameliorating NASH and NASH-HCC, and as such, in-depth understanding of the functions and molecular attributes of this molecule is essential. Conclusion: The present study unravels the unique role of the LXXLL motif in mediating the balance between the metabolic and oncogenic functions of AEG-1. (Hepatology Communications 2022;6:561-575).N uclear receptors mediate the action of vitamins, hormones and lipids, and function as key regulators of cell growth, differentiation, metabolism, and development. (1) These receptors are ligand-dependent transcription factors that, upon ligand-binding, recruit transcription coactivators to induce target gene transcription. The coactivators are histone acetyltransferases (HATs) that interact with the transcription factors using a specific LXXLL motif. (2) This motif is crucial for induction of nuclear receptor-mediated transcription to regulate a plethora of physiological activities. The presence of LXXLL

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.

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