SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3′, 5′-deoxythymidine bisphosphate (pdTp) inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation, and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC.

Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established mandating more in-depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) in NASH using a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) and a conditional hepatocyte-specific AEG-1 knockout mouse (AEG-1ΔHEP). Alb/AEG-1 mice developed spontaneous NASH while AEG-1ΔHEP mice were protected from high fat diet (HFD)-induced NASH. Intriguingly, AEG-1 overexpression was observed in livers of NASH patients and WT mice that developed steatosis upon feeding high fat diet. In-depth molecular analysis unraveled that inhibition of PPARα activity resulting in decreased fatty acid β-oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased NF-κB-mediated inflammation act in concert to mediate AEG-1-induced NASH. Therapeutically, hepatocyte-specific nanoparticle-delivered AEG-1 siRNA provided marked protection from HFD-induced NASH in wild-type mice. Conclusion AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients.

Activation of IGF signaling is a major oncogenic event in diverse cancers, including hepatocellular carcinoma (HCC). In this setting, the insulin-like growth factor binding protein IGFBP7 inhibits IGF signaling by binding the IGF-1 receptor (IGF-1R), functioning as a candidate tumor suppressor. IGFBP7 abrogates tumors by inhibiting angiogenesis and inducing cancer-specific senescence and apoptosis. Here we report that Igfbp7-deficient mice exhibit constitutively active IGF signaling, presenting with pro-inflammatory and immunosuppressive microenvironments and spontaneous liver and lung tumors occurring with increased incidence in carcinogen-treated subjects. Igfbp7 deletion increased proliferation and decreased senescence of hepatocytes and mouse embryonic fibroblasts, effects that were blocked by treatment with IGF-1 receptor inhibitor. Significant inhibition of genes regulating immune surveillance was observed in Igfbp7−/− murine livers, which was associated with a marked inhibition in antigen cross-presentation by Igfbp7−/− dendritic cells. Conversely, IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immunocompetent mice. Depletion of CD4+ or CD8+ T lymphocytes abolished this growth inhibition, identifying it as an immune-mediated response. Our findings define an immune component of the pleiotropic mechanisms through which IGFBP7 suppresses HCC. Furthermore, they offer a genetically based preclinical proof of concept for IGFBP7 as a therapeutic target for immune management of HCC.

Staphylococcal nuclease and tudor domain containing 1 (SND1) is overexpressed in multiple cancers, including hepatocellular carcinoma (HCC), and functions as an oncogene. This study was carried out to identify novel SND1-interacting proteins to better understand its molecular mechanism of action. SND1-interacting proteins were identified by a modified yeast two-hybrid assay. Protein-protein interaction was confirmed by co-immunoprecipitation analysis. Staphylococcal nuclease and tudor domain containing 1 (SND1) is a multifunctional protein regulating transcription, RNA interference (RNAi) and mRNA splicing, editing, and stability and functions as an oncogene in multiple cancers (1). SND1 overexpression has been observed in cancers of liver, colon, breast, brain, and prostate, and overexpression and knockdown studies have confirmed that SND1 promotes the hallmarks of cancer, such as proliferation, invasion, epithelialmesenchymal transition, angiogenesis, and metastasis (2-8).As a pleiotropic protein, SND1 promotes tumorigenesis in multiple ways. We documented that SND1 promotes RNA-induced silencing complex activity in hepatocellular carcinoma (HCC) 4 cells thus facilitating oncogenic miRNA-mediated degradation of tumor suppressor mRNAs and thereby facilitating hepatocarcinogenesis (2). In HCC cells, SND1 promotes angiogenesis by activating a linear pathway involving NF-B, miRNA-221, angiogenin, and CXCL16, and it promotes epithelial-mesenchymal transition via angiotensin II type 1 receptor (AT1R) and TGF␤ signaling pathway (7,8). Studies in breast cancer cells have identified SND1 as a downstream target of TGF␤ signaling where it promotes metastasis by increasing E3 ubiquitin ligase Smurf1 leading to RhoA ubiquitination and degradation (9). Additionally SND1 is required for expansion and activity of tumor-initiating cells in the breast cancer model (6). In colon cancer cells, SND1 promotes tumorigenesis by activating Wnt/␤-catenin pathway (4). SND1 functions as an anti-apoptotic protein, and cleavage of SND1 by caspases is necessary during drug-induced apoptosis (10). These findings indicate that SND1 promotes tumorigenesis by diverse mechanisms, and more in-depth studies are necessary to better understand the molecular mechanisms by which SND1 exerts its oncogenic function.Triglycerides are broken down into fatty acids and glycerol by sequential action of multiple enzymes (11). Triglyceride lipase breaks down triglyceride into diacylglycerols, which are further broken down to monoacylglycerols by hormone-sensitive lipase. Monoglyceride lipase (MGLL) finally breaks down