Pretreatment up-regulation of hepatic interferon (IFN)-stimulated genes (ISGs) has a stronger association with the treatment-resistant interleukin (IL)28B minor genotype (MI; TG/GG at rs8099917) than with the treatment-sensitive IL28B major genotype (MA; TT at rs8099917). We compared the expression of ISGs in the liver and blood of 146 patients with chronic hepatitis C who received pegylated IFN and ribavirin combination therapy. Gene expression profiles in the liver and blood of 85 patients were analyzed using an Affymetrix GeneChip (Affymetrix, Santa Clara, CA). ISG expression was correlated between the liver and blood of the MA patients, whereas no correlation was observed in the MI patients. This loss of correlation was the result of the impaired infiltration of immune cells into the liver lobules of MI patients, as demonstrated by regional gene expression analysis in liver lobules and portal areas using laser capture microdissection and immunohistochemical staining. Despite having lower levels of immune cells, hepatic ISGs were up-regulated in the liver of MI patients and they were found to be regulated by multiple factors, namely, IL28A/B, IFN-k4, and wingless-related MMTV integration site 5A (WNT5A). Interestingly, WNT5A induced the expression of ISGs, but also increased hepatitis C virus replication by inducing the expression of the stress granule protein, GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1), in the Huh-7 cell line. In the liver, the expression of WNT5A and its receptor, frizzled family receptor 5, was significantly correlated with G3BP1. Conclusions: Immune cells were lost and induced the expression of other inflammatory mediators, such as WNT5A, in the liver of IL28B minor genotype patients. This might be related to the high level of hepatic ISG expression in these patients and the treatment-resistant phenotype of the IL28B minor genotype. (HEPATOLOGY 2014;59:828-838)

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Malnutrition in the advanced fibrosis stage of chronic hepatitis C (CH‐C) impairs interferon (IFN) signaling by inhibiting mammalian target of rapamycin complex 1 (mTORC1) signaling. However, the effect of profibrotic signaling on IFN signaling is not known. Here, the effect of transforming growth factor (TGF)‐β signaling on IFN signaling and hepatitis C virus (HCV) replication was examined in Huh‐7.5 cells by evaluating the expression of forkhead box O3A (Foxo3a), suppressor of cytokine signaling 3 (Socs3), c‐Jun, activating transcription factor 2, ras homolog enriched in brain, and mTORC1. The findings were confirmed in liver tissue samples obtained from 91 patients who received pegylated‐IFN and ribavirin combination therapy. TGF‐β signaling was significantly up‐regulated in the advanced fibrosis stage of CH‐C. A significant positive correlation was observed between the expression of TGF‐β2 and mothers against decapentaplegic homolog 2 (Smad2), Smad2 and Foxo3a, and Foxo3a and Socs3 in the liver of CH‐C patients. In Huh‐7.5 cells, TGF‐β1 activated the Foxo3a promoter through an AP1 binding site; the transcription factor c‐Jun was involved in this activation. Foxo3a activated the Socs3 promoter and increased HCV replication. TGF‐β1 also inhibited mTORC1 and IFN signaling. Interestingly, c‐Jun and TGF‐β signaling was up‐regulated in treatment‐resistant IL28B minor genotype patients (TG/GG at rs8099917), especially in the early fibrosis stage. Branched chain amino acids or a TGF‐β receptor inhibitor canceled these effects and showed an additive effect on the anti‐HCV activity of direct‐acting antiviral drugs (DAAs). Conclusion: Blocking TGF‐β signaling could potentiate the antiviral efficacy of IFN‐ and/ or DAA‐based treatment regimens and would be useful for the treatment of difficult‐to‐cure CH‐C patients. (Hepatology 2014;60:1519–1530)

Highlights d SeP, a hepatokine causing insulin resistance, is increased in HCV patients d SeP mRNA binds to RIG-I and inhibits RIG-I-mediated type I IFN immune responses d The full-length structure of SEPP1 mRNA is required to regulate RIG-I activity d Increased serum SeP in chronic hepatitis C patients is associated with DAAs failure

Sphingosine-1-phospate is a potent bioactive lipid metabolite that regulates cancer progression. Because sphingosine kinase 1 and sphingosine kinase 2 (SPHK 1/2) are both essential for sphingosine-1-phospate production, they could be a therapeutic target in various cancers. Peretinoin, an acyclic retinoid, inhibits post-therapeutic recurrence of hepatocellular carcinoma via unclear mechanisms. In this study, we assessed effects of peretinoin on SPHK expression and liver cancer development in vitro and in vivo. We examined effects of peretinoin on expression, enzymatic and promoter activity of SPHK1 in a human hepatoma cell line, Huh-7. We also investigated effects of SPHK1 on hepatocarcinogenesis induced by diethylnitrosamine using SPHK1 knockout mice. Peretinoin treatment of Huh-7 cells reduced mRNA levels, protein expression and enzymatic activity of SPHK1. Peretinoin reduced SPHK1 promoter activity; this effect of peretinoin was blocked by overexpression of Sp1, a transcription factor. Deletion of all Sp1 binding sites within the SPHK1 promoter region abolished SPHK1 promoter activity, suggesting that peretinoin reduced mRNA levels of SPHK1 via Sp1. Additionally, diethylnitrosamine-induced hepatoma was fewer and less frequent in SPHK1 knockout compared to wild-type mice. Our data showed crucial roles of SPHK1 in hepatocarcinogenesis and suggests that peretinoin prevents hepatocarcinogenesis by suppressing mRNA levels of SPHK1.Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the second most common cause of cancer death, estimated to be responsible for 745,000 deaths in 2012 1 . Infection with hepatitis B virus and/or hepatitis C virus (HCV) is a major cause of HCC 2-4 . Due to dramatic progress in antiviral treatments, hepatitis viral infection is now much easier to control. In particular, highly efficient direct-acting antiviral agents can eliminate HCV from the infected liver in more than 90% of cases 5 . However, considerable time is required for the liver to fully recover from liver cirrhosis and HCC is reported to emerge from HCV-infected livers at a rate of about 1% per year, even after HCV is successfully eliminated [6][7][8] . HCC can be treated by means of ablation, surgical resection, catheter embolization, chemotherapy, and liver transplantation, depending on HCC stage and liver function. Curative resection or ablation is applied to early-stage HCC but the 3-year recurrence rate after curative treatment in the general population is 50% 9,10 . Moreover, the recurrence rate is >70% in HCV-infected patients 11 . Therefore, new therapeutic strategies to prevent HCC recurrence or hepatocarcinogenesis are urgently needed.Peretinoin (generic name code: NIK-333), which was developed by Kowa Company, Ltd. (Aichi, Japan), is an orally available acyclic retinoid with a vitamin A-like structure that targets retinoid nuclear receptors, such as retinoid X receptor (RXR) and retinoic acid receptor (RAR) 12 . Administration of peretinoin significantly reduces the incidence of post-thera...