K Sugiyama

Keio University, Edo, Tōkyō, Japan

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Publications (153)403.26 Total impact

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    ABSTRACT: Nonalcoholic steatohepatitis (NASH) has emerged as a common cause of chronic liver disease and virus-independent hepatocellular carcinoma (HCC) in patients with obesity, diabetes and metabolic syndrome. To reveal the molecular mechanism underlying hepatocarcinogenesis from NASH, microRNA (miRNA) expression profiles were analyzed in STAM mice, a NASH-HCC animal model. miRNA expression was also examined in 42 clinical samples of HCC tissue. Histopathological images of the liver of STAM mice at the ages of 6, 8, 12 and 18 weeks showed findings compatible with fatty liver, NASH, liver cirrhosis (LC), and HCC, respectively. miR-122 expression in non-tumor LC at the age of 18 weeks was significantly lower than that in LC at the age of 12 weeks. miR-122 expression was further decreased in HCCs relative to non-tumor LC at the age of 18 weeks. miR-122 expression was also decreased in clinical samples of both liver tissue showing macrovesicular steatosis and HCC, being consistent with the findings in the NASH model mice. DNA methylation analysis revealed that silencing of miR-122 was not mediated by DNA hypermethylation of the promoter region. These results suggest that silencing of miR-122 is an early event during hepatocarcinogenesis from NASH, and that miR-122 could be a novel molecular marker for evaluating the risk of HCC in patients with NASH.This article is protected by copyright. All rights reserved.
    Cancer Science 08/2014; · 3.48 Impact Factor
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    ABSTRACT: Nonalcoholic steatohepatitis (NASH) has emerged as a common cause of chronic liver disease and virus-independent hepatocellular carcinoma (HCC) in patients with obesity, diabetes and metabolic syndrome. To reveal the molecular mechanism underlying hepatocarcinogenesis from NASH, microRNA (miRNA) expression profiles were analyzed in STAM mice, a NASH-HCC animal model. miRNA expression was also examined in 42 clinical samples of HCC tissue. Histopathological images of the liver of STAM mice at the ages of 6, 8, 12 and 18 weeks showed findings compatible with fatty liver, NASH, liver cirrhosis (LC), and HCC, respectively. miR-122 expression in non-tumor LC at the age of 18 weeks was significantly lower than that in LC at the age of 12 weeks. miR-122 expression was further decreased in HCCs relative to non-tumor LC at the age of 18 weeks. miR-122 expression was also decreased in clinical samples of both liver tissue showing macrovesicular steatosis and HCC, being consistent with the findings in the NASH model mice. DNA methylation analysis revealed that silencing of miR-122 was not mediated by DNA hypermethylation of the promoter region. These results suggest that silencing of miR-122 is an early event during hepatocarcinogenesis from NASH, and that miR-122 could be a novel molecular marker for evaluating the risk of HCC in patients with NASHThis article is protected by copyright. All rights reserved.
    Cancer Science 08/2014; · 3.48 Impact Factor
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    ABSTRACT: Acyl-coenzyme A: cholesterol acyltransferase (ACAT) catalyzes the conversion of free cholesterol (FC) to cholesterol ester, which prevents excess accumulation of FC. We recently found that FC accumulation in hepatic stellate cells (HSCs) plays a role in progression of liver fibrosis, but the effect of ACAT1 on liver fibrosis has not been clarified. In this study, we aimed to define the role of ACAT1 in the pathogenesis of liver fibrosis. ACAT1-deficient and wild-type mice, or Toll-like receptor 4 (TLR4)(-/-)ACAT1(+/+) and TLR4(-/-)ACAT1(-/-) mice were subjected to bile duct ligation (BDL) for 3 weeks or were given carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis. ACAT1 was the major isozyme in mice and human primary HSCs, and ACAT2 was the major isozyme in mouse primary hepatocytes and Kupffer cells. ACAT1 deficiency significantly exaggerated liver fibrosis in the mouse models of liver fibrosis, without affecting the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation. ACAT1 deficiency significantly increased FC levels in HSCs, augmenting TLR4 protein and downregulating expression of transforming growth factor-β (TGFβ) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of HSCs to TGFβ activation. Exacerbation of liver fibrosis by ACAT1 deficiency was dependent on FC accumulation-induced enhancement of TLR4 signaling. ACAT1 deficiency exaggerates liver fibrosis mainly through enhanced FC accumulation in HSCs. Regulation of ACAT1 activities in HSCs could be a target for treatment of liver fibrosis.
    Journal of Hepatology 03/2014; · 9.86 Impact Factor
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    ABSTRACT: Most of experiments for HCV infection have been done using lytic infection systems, in which HCV-infected cells inevitably die. Here, to elucidate metabolic alteration in HCV-infected cells in a more stable condition, we established an HCV-persistently-infected cell line, designated as HPI cells. This cell line has displayed prominent steatosis and supported HCV infection for more than 2 years, which is the longest ever reported. It enabled us to analyze metabolism in the HCV-infected cells integrally combining metabolomics and expression arrays. It revealed that rate-limiting enzymes for biosynthesis of cholesterol and fatty acids were up-regulated with actual increase in cholesterol, desmosterol (cholesterol precursor) and pool of fatty acids. Notably, the pentose phosphate pathway was facilitated with marked up-regulation of glucose-6-phosphate dehydrogenase, a rete-limiting enzyme, with actual increase in NADPH. In its downstream, enzymes for purine synthesis were also up-regulated resulting in increase of purine. Contrary to common cancers, the TCA cycle was preferentially facilitated comparing to glycolysis pathway with a marked increase of most of amino acids. Interestingly, some genes controlled by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master regulator of antioxidation and metabolism, were constitutively up-regulated in HPI cells. Knockdown of Nrf2 markedly reduced steatosis and HCV infection, indicating that Nrf2 and its target genes play important roles in metabolic alteration and HCV infection. In conclusion, HPI cell is a bona fide HCV-persistently-infected cell line supporting HCV infection for years. This cell line sustained prominent steatosis in a hypermetabolic status producing various metabolites. Therefore, HPI cell is a potent research tool not only for persistent HCV infection but also for liver metabolism, overcoming drawbacks of the lytic infection systems.
    PLoS ONE 01/2014; 9(4):e94460. · 3.53 Impact Factor
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    ABSTRACT: Although nonalcoholic steatohepatitis (NASH) is associated with hypercholesterolemia, the underlying mechanisms of this association have not been clarified. We aimed to elucidate the precise role of cholesterol in the pathophysiology of NASH. C57BL/6 mice were fed a control, high-cholesterol (HC), methionine-choline-deficient (MCD), or MCD+HC diet for 12 wk or a control, HC, high-fat (HF), or HF+HC diet for 24 wk. Increased cholesterol intake accelerated liver fibrosis in both the mouse models without affecting the degree of hepatocellular injury or Kupffer cell activation. The major causes of the accelerated liver fibrosis involved free cholesterol (FC) accumulation in hepatic stellate cells (HSCs), which increased Toll-like receptor 4 protein (TLR4) levels through suppression of the endosomal-lysosomal degradation pathway of TLR4, and thereby sensitized the cells to transforming growth factor (TGF)β-induced activation by downregulating the expression of bone morphogenetic protein and activin membrane-bound inhibitor. Mammalian-cell cholesterol levels are regulated via a feedback mechanism mediated by sterol regulatory element-binding protein 2 (SREBP2), maintaining cellular cholesterol homeostasis. Nevertheless, HSCs were sensitive to FC accumulation because the high intracellular expression ratio of SREBP cleavage-activating protein (Scap) to insulin-induced gene (Insig) disrupted the SREBP2-mediated feedback regulation of cholesterol homeostasis in these cells. HSC activation subsequently enhanced the disruption of the feedback system by Insig-1 downregulation. In addition, the suppression of peroxisome proliferator-activated receptor γ signaling accompanying HSC activation enhanced both SREBP2 and microRNA-33a signaling. Consequently, FC accumulation in HSCs increased and further sensitized these cells to TGFβ-induced activation in a vicious cycle, leading to exaggerated liver fibrosis in NASH. Conclusion: These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH. (Hepatology 2013;).
    Hepatology 07/2013; · 12.00 Impact Factor
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    ABSTRACT: Inflammatory cytokines and chemokines play important roles in inflammation during viral infection. Hepatitis C virus (HCV) is a hepatotropic RNA virus that is closely associated with chronic liver inflammation, fibrosis and hepatocellular carcinoma. During the progression of HCV-related diseases, hepatic stellate cells (HSCs) contribute to the inflammatory response triggered by HCV infection. However, the underlying molecular mechanisms that mediate HSC-induced chronic inflammation during HCV infection are not fully understood. By co-culturing HSCs with HCV-infected hepatocytes in vitro, we found that HSCs stimulated HCV-infected hepatocytes, leading to the expression of proinflammatory cytokines and chemokines such as IL-6, IL-8, MIP-1α and MIP-1β. Moreover, we found that this effect was mediated by IL-1α, which was secreted by HSCs. HCV infection enhanced production of CCAAT/enhancer binding protein (C/EBP) β mRNA, and HSC-dependent IL-1α production contributed to the stimulation of C/EBPβ target cytokines and chemokines in HCV-infected hepatocytes. Consistent with this result, knock-down of mRNA for C/EBPβ in HCV-infected hepatocytes resulted in decreased production of cytokines and chemokines after the addition of HSC-conditioned medium. Induction of cytokines and chemokines in hepatocytes by the HSC-conditioned medium required a yet to be identified post-entry event during productive HCV infection. The cross-talk between HSCs and HCV-infected hepatocytes is a key feature of inflammation-mediated, HCV-related diseases.
    Journal of Virology 05/2013; · 5.08 Impact Factor
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    ABSTRACT: The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) has a clinical promise for treatment of cancer including hepatocellular carcinoma (HCC). To investigate effect of SAHA on hepatitis C virus (HCV) replication, we treated the HCV replicon cell OR6 with SAHA. HCV replication was significantly inhibited by SAHA at concentrations below 1 μM with no cellular toxicity. Another HDAC inhibitor, tricostatin A, also showed reduction of HCV replication. The microarray analysis and quantitative RT-PCR demonstrated up-regulation of osteopontin (OPN) and down-regulation of apolipoprotein-A1 (Apo-A1) after SAHA treatment. Direct gene induction of OPN and knockdown of Apo-A1 also showed reduction of HCV replication. The liver specific microRNA-122, which is involved in HCV replication, was not affected by SAHA treatment. These results suggest that SAHA has suppressive effect on HCV replication through alterations of gene expression such as OPN and Apo-A1 in host cells. Epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for diseases associated with HCV infection such as chronic hepatitis, liver cirrhosis, and HCC. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 03/2013; · 3.06 Impact Factor
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    ABSTRACT: Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. We recently demonstrated that C-C motif chemokine receptor (CCR) 9+ macrophages are crucial in the pathogenesis of acute liver inflammation. However, the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed tumor necrosis factor (TNF)-α-producing CCR9+ macrophages accumulated during the initiation of carbon tetrachloride (CCl4 )-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9+ macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9-/- mice compared with wild-type (WT) mice, assessed by α-smooth muscle actin (α-SMA) immunostain, sirius red staining and mRNA expression levels of α-SMA, collagen 1α1, transforming growth factor (TGF)-β1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b+ macrophages in CCl4 -treated WT mice showed marked increases in TNF, NO synthase-2 and TGF-β1 mRNA expression compared with CCR9-/- mice, implying pro-inflammatory and profibrogenic properties. Hepatic CD11b+ macrophages from CCl4 -treated WT mice (i.e. CCR9+ macrophages), but not CD8+ T lymphocytes or non-CD11b+ cells, significantly activated HSCs in vitro compared with those from CCR9-/- mice. TNF-α or TGF-β1 antagonism attenuated CCR9+ macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. Conclusion: Accumulated CD11b+ macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis. (HEPATOLOGY 2013.).
    Hepatology 03/2013; · 12.00 Impact Factor
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    ABSTRACT: The tumor suppressor p53 is a primary sensor of stressful stimuli, controlling a number of biologic processes. The aim of our study was to examine the roles of p53 in non-alcoholic steatohepatitis (NASH). Male wild type and p53-deficient mice were fed a methionine- and choline-deficient diet for 8weeks to induce nutritional steatohepatitis. mRNA expression profiles in normal liver samples and liver samples from patients with non-alcoholic liver disease (NAFLD) were also evaluated. Hepatic p53 and p66Shc signaling was enhanced in the mouse NASH model. p53 deficiency suppressed the enhanced p66Shc signaling, decreased hepatic lipid peroxidation and the number of apoptotic hepatocytes, and ameliorated progression of nutritional steatohepatitis. In primary cultured hepatocytes, transforming growth factor (TGF)-β treatment increased p53 and p66Shc signaling, leading to exaggerated reactive oxygen species (ROS) accumulation and apoptosis. Deficient p53 signaling inhibited TGF-β-induced p66Shc signaling, ROS accumulation, and hepatocyte apoptosis. Furthermore, expression levels of p53, p21, and p66Shc were significantly elevated in human NAFLD liver samples, compared with results obtained with normal liver samples. Among NAFLD patients, those with NASH had significantly higher hepatic expression levels of p53, p21, and p66Shc compared with the group with simple steatosis. A significant correlation between expression levels of p53 and p66Shc was observed. p53 in hepatocytes regulates steatohepatitis progression by controlling p66Shc signaling, ROS levels, and apoptosis, all of which may be regulated by TGF-β. Moreover, p53/p66Shc signaling in the liver appears to be a promising target for the treatment of NASH.
    Journal of Hepatology 05/2012; 57(4):837-43. · 9.86 Impact Factor
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    ABSTRACT: Some studies have indicated that dietary cholesterol has a role in the progression of liver fibrosis. We investigated the mechanisms by which dietary cholesterol might contribute to hepatic fibrogenesis. C57BL/6 mice were fed a high-cholesterol diet or a control diet for 4 weeks; liver fibrosis then was induced by bile-duct ligation or carbon tetrachloride administration. Hepatic stellate cells (HSCs) were isolated from mice fed high-cholesterol diets or from Niemann-Pick type C1-deficient mice, which accumulate intracellular free cholesterol. After bile-duct ligation or carbon tetrachloride administration, mice fed high-cholesterol diets had significant increases in liver fibrosis and activation of HSCs compared with mice fed control diets. There were no significant differences in the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation, between mice fed high-cholesterol or control diets. Levels of free cholesterol were much higher in HSCs from mice fed high-cholesterol diets than those fed control diets. In cultured HSCs, accumulation of free cholesterol in HSCs increased levels of Toll-like receptor 4 (TLR4), leading to down-regulation of bone morphogenetic protein and activin membrane-bound inhibitor (a pseudoreceptor for transforming growth factor [TGF]β); the HSCs became sensitized to TGFβ-induced activation. Liver fibrosis was not aggravated by the high-cholesterol diet in C3H/HeJ mice, which express a mutant form of TLR4; HSCs that express mutant TLR4 were not activated by accumulation of free cholesterol. Dietary cholesterol aggravates liver fibrosis because free cholesterol accumulates in HSCs, leading to increased TLR4 signaling, down-regulation of bone morphogenetic protein and activin membrane-bound inhibitor, and sensitization of HSC to TGFβ. This pathway might be targeted by antifibrotic therapies.
    Gastroenterology 01/2012; 142(1):152-164.e10. · 12.82 Impact Factor
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    ABSTRACT: Heat-shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of various transcription factors and protein kinases in signal transduction. The hepatitis C virus (HCV) internal ribosome entry site (IRES) RNA drives translation by directly recruiting the 40S ribosomal subunits that bind to eukaryotic initiation factor 3 (eIF3). Our data indicate that Hsp90 binds indirectly to eIF3 subunit c by interacting with it through the HCV IRES RNA, and the functional consequence of this Hsp90-eIF3c-HCV-IRES RNA interaction is the prevention of ubiquitination and the proteasome-dependent degradation of eIF3c. Hsp90 activity interference by Hsp90 inhibitors appears to be the result of the dissociation of eIF3c from Hsp90 in the presence of HCV IRES RNA and the resultant induction of the degradation of the free forms of eIF3c. Moreover, the interaction between Hsp90 and eIF3c is dependent on HCV IRES RNA binding. Furthermore, we demonstrate, by knockdown of eIF3c, that the silencing of eIF3c results in inhibitory effects on translation of HCV-derived RNA but does not affect cap-dependent translation. These results indicate that the interaction between Hsp90 and eIF3c may play an important role in HCV IRES-mediated translation.
    Virus Research 01/2012; 163(1):390-5. · 2.75 Impact Factor
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    ABSTRACT: Many chronic hepatitis patients with hepatitis C virus (HCV) are observed to have a degree of steatosis which is a factor in the progression of liver diseases. Transgenic mice expressing HCV core protein develop liver steatosis before the onset of hepatocellular carcinoma, suggesting active involvement of HCV in the de-regulation of lipid metabolism in host cells. However, the role of lipid metabolism in HCV life cycle has not been fully understood until the establishment of in vitro HCV infection and replication system. In this review we focus on HCV production with regard to modification of lipid metabolism observed in an in vitro HCV infection and replication system. The importance of lipid droplet to HCV production has been recognized, possibly at the stage of virus assembly, although the precise mechanism of lipid droplet for virus production remains elusive. Association of lipoprotein with HCV in circulating blood in chronic hepatitis C patients is observed. In fact, HCV released from culture medium is also associated with lipoprotein. The fact that treatment of HCV fraction with lipoprotein lipase (LPL) abolished infectivity indicates the essential role of lipoprotein's association with virus particle in the virus life cycle. In particular, apolipoprotein E (ApoE), a component of lipoprotein associated with HCV plays a pivotal role in HCV infectivity by functioning as a virus ligand to lipoprotein receptor that also functions as HCV receptor. These results strongly suggest the direct involvement of lipid metabolism in the regulation of the HCV life cycle.
    Current opinion in virology. 07/2011; 1(1):19-26.
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    ABSTRACT: The effect of lipolysis by lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) on hepatitis C virus (HCV) infection was evaluated. First, medium from HuH7.5 cells bearing HCV genome replication was treated with LPL. LPL treatment led to reduced HCV infectivity, shifted HCV to higher densities, and lowered the amount of apolipoprotein E-associated HCV. The effect of endogenous HTGL secreted from HuH7.5 on HCV infectivity was next examined. Neutralization of HTGL by an anti-HTGL antibody resulted in suppression of LPL-induced reduction in infectivity of HCV-bearing medium, while knockdown of HTGL by siRNA led to increased HCV infectivity irrespective of LPL. HCV in medium from HTGL knockdown cells was found in fractions with a lower density. These results indicate that changes in the nature of HCV-associated lipoproteins by LPL and/or HTGL affect HCV infectivity, suggesting that association of HCV with specific lipoproteins is important for HCV infectivity.
    Virology 11/2010; 407(1):152-9. · 3.35 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) is a causative agent of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV in circulating blood associates with lipoproteins such as very low density lipoprotein (VLDL) and low-density lipoprotein (LDL). Although these associations suggest that lipoproteins are important for HCV infectivity, the roles of lipoproteins in HCV production and infectivity are not fully understood. To clarify the roles of lipoprotein in the HCV life cycle, we analyzed the effect of apolipoprotein E (ApoE), a component of lipoprotein, on virus production and infectivity. The production of infectious HCV was significantly reduced by the knockdown of ApoE. When an ApoE mutant that fails to be secreted into the culture medium was used, the amount of infectious HCV in the culture medium was dramatically reduced; the infectious HCV accumulated inside these cells, suggesting that infectious HCV must associate with ApoE prior to virus release. We performed rescue experiments in which ApoE isoforms were ectopically expressed in cells depleted of endogenous ApoE. The ectopic expression of the ApoE2 isoform, which has low affinity for the LDL receptor (LDLR), resulted in poor recovery of infectious HCV, whereas the expression of other isoforms, ApoE3 and ApoE4, rescued the production of infectious virus, raising it to an almost normal level. Furthermore, we found that the infectivity of HCV required both the LDLR and scavenger receptor class B, member I (SR-BI), ligands for ApoE. These findings indicate that ApoE is an essential apolipoprotein for HCV infectivity.
    Journal of Virology 11/2010; 84(22):12048-57. · 5.08 Impact Factor
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    ABSTRACT: Replication and infectivity of hepatitis C virus (HCV) with a defective genome is ambiguous. We molecularly cloned 38 HCV isolates with defective genomes from 18 patient sera. The structural regions were widely deleted, with the 5' untranslated, core, and NS3-NS5B regions preserved. All of the deletions were in frame, indicating that they are translatable to the authentic terminus. Phylogenetic analyses showed self-replication of the defective genomes independent of full genomes. We generated a defective genome of chimeric HCV to mimic the defective isolate in the serum. By using this, we demonstrated for the first time that the defective genome, as it is circulating in the blood, can be encapsidated as an infectious particle by trans complementation of the structural proteins.
    Journal of Virology 05/2009; 83(13):6922-8. · 5.08 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) establishes a persistent infection and causes chronic hepatitis. Chronic hepatitis patients often develop hepatic cirrhosis and progress to liver cancer. The development of this pathological condition is linked to the persistent infection of the virus. In other words, viral replication/multiplication may contribute to disease pathology. Accumulating clinical studies suggest that HCV infection alters lipid metabolism, and thus causes fatty liver. It has been reported that this abnormal metabolism exacerbates hepatic diseases. Recently, we revealed that lipid droplets play a key role in HCV replication. Understanding the molecular mechanism of HCV replication will help elucidate the pathogenic mechanism and develop preventive measures that inhibit disease manifestation by blocking persistent infection. In this review, we outline recent findings on the function of lipid droplets in the HCV replication cycle and describe the relationship between the development of liver diseases and virus replication.
    Proceedings of the Japan Academy Ser B Physical and Biological Sciences 02/2009; 85(7):217-28. · 2.77 Impact Factor
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    ABSTRACT: Forty seven patients with early gastric cancer received a 30-minute intravenous injection of bromodeoxyuridine (BrdU), 1000 mg each 1 hour before laparotomy, to label tumor cells in the S phase. In 13 of 47 patients, specimens obtained by endoscopic biopsy were cultured in vitro at 37°C for 1 hour under three times the atmospheric pressure in a vial with 400 μM BrdU. Labeled cells were detected in the resected specimen and the cultured specimen by immunohistochemical staining procedure. The BrdU labeling index (LI, defined as the percentage of labeled cells in relation to the 1000 tumor cells) was calculated for each specimen. All patients without lymph node metastasis had an in vivo BrdU LI of less than 12%. In contrast, 31% of patients with early gastric cancer with an in vivo BrdU LI greater than 12% had lymph node metastasis. There was a correlation between the in vivo and the in vitro LI. Therefore, the in vitro BrdU LI of specimens obtained by endoscopic biopsy may be a useful indicator of lymph node status in patients with individual early gastric cancers before operations. If the in vitro BrdU LI is less than 12%, lymph node dissection may not be necessary.
    Cancer 06/2006; 64(8):1665 - 1668. · 5.20 Impact Factor
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    ABSTRACT: Analysis of DNA ploidy patterns was performed on 129 cases of primary gastric cancer and the results were correlated with histologic findings and in vivo bromodeoxyuridine (BrdU) labeling. Forty-nine cases were diploid (38%) and 80 cases were aneuploid (62%). There was no correlation between DNA ploidy and histologic type. In aneuploid tumors, incidence of lymphatic invasion, lymph node metastasis, and rate of advanced cases were significantly higher than those in diploid tumors. During the follow-up period of 5 to 10 years, 23 of 40 patients (55%) with aneuploid tumors died of disease within 3 to 120 months. Only 13 of 36 patients (36%) with diploid tumors died of disease. The BrdU labeling indices (BrdU LI) ranged from 2.8% to 26.7%, with a mean of 10.4%. There was no correlation between BrdU LI and histologic type or stage. The mean BrdU LI of early cancers was 8.1%. The mean BrdU LI of advanced cancers was 11.9%. The BrdU LI of cancers with lymphatic invasion or lymph node metastasis was higher than those without them. The mean BrdU LI of diploid cancers was 6.0%. The mean BrdU LI of aneuploid cancers was 11.9%. There was a good correlation between BrdU LI and DNA ploidy patterns. These results indicate that DNA ploidy patterns and BrdU LI may possibly be useful prognostic markers for gastric cancers.
    Cancer 06/2006; 62(8):1497 - 1502. · 5.20 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor C (VEGF-C) is the only factor known causing lymphangiogenesis. We report herein the review of recent experimental studies on VEGF family and their receptors and the molecular mechanisms of the lymphangiogenesis in cancer. According to our study, VEGF-C is a potent stimulator in not only the angiogenesis but also the lymphangiogenesis on the chick chorioallantoic membrane. In the clinical specimens from gastric cancer, there is an intimate relationship between the VEGF receptor-3/VEGF-C tissue status and lymphagiogenesis. RT-PCR and immunohistological examinations demonstrated that VEGF-C was mainly produced from cancer cells and that VEGFR-3 expression was restricted in the endothelial cells of lymphatic vessels. VEGF-C and VEGFR-3 mRNA expression were positively correlated in primary gastric cancers and the number of VEGFR-3 positive lymphatic vessels in VEGF-C mRNA positive tumour was significantly larger than that in VEGF-C negative tumours. The number of such vessels in tumour stroma was closely related to the grade of lymphatic invasion of gastric cancer. Accordingly, we conclude that VEGF-C may induce the lymphatic neogenesis in the stroma of primary gastric cancer. In these circumstances, cancer cells can easily intravasate into the lymphatic vessels, because of the increase of the contact point of cancer cells with lymphatic vessels.
    04/2006: pages 223-239;
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    ABSTRACT: Based on epidemiological evidence, hepatitis C virus (HCV) is thought to be involved in the etiology of not only hepatocellular carcinoma, but also lymphoproliferative diseases. In addition, our previous studies using recently developed cell culture systems that support HCV replication have indicated that HCV possesses both hepatotropism and lympholropism. To determine whether HCV is present in extrahepatic organs, we conducted semi-quantitative reverse transcription-polymerase chain reaction for the 5 non-coding region of the HCV genome in surgical specimens (lymph nodes, ovary, uterus, peripheral blood mononuclear cells [PBMCs] and serum) from three patients with gynecological cancer. We found relatively high HCV genome titers in the lymph nodes, not in the sera, irrespective of various titers in PBMCs. These results suggest that lymph nodes may play an important role in the carrier state and the persistence of HCV infection. Moreover, contrary to expectation, high titers of the HCV genome were observed in the ovaries and the uteri, suggesting the feasibility of mother-toinfant and spouse-to-spouse transmissions of HCV.
    Cancer Science 08/2005; 88(10):925 - 927. · 3.48 Impact Factor

Publication Stats

3k Citations
403.26 Total Impact Points

Institutions

  • 2009–2014
    • Keio University
      • • Department of Internal Medicine
      • • Center for Integrated Medical Research
      Edo, Tōkyō, Japan
  • 2013
    • National Center for Global Health and Medicine in Japan
      Tiba, Chiba, Japan
  • 2012–2013
    • National Defense Medical College
      • Department of Internal Medicine
      Tokorozawa, Saitama-ken, Japan
  • 2009–2011
    • Chiba Institute of Technology
      • Department of Life and Environmental Sciences
      Narashino, Chiba-ken, Japan
  • 2003
    • Okayama University
      • Department of Molecular Biology and Biochemistry
      Okayama, Okayama, Japan
  • 1995–2003
    • National Cancer Center, Japan
      Edo, Tōkyō, Japan
  • 2002
    • Kyoto University
      • Institute for Virus Research
      Kyoto, Kyoto-fu, Japan
  • 1987–2002
    • Hamamatsu University School of Medicine
      • Department of Neurosurgery
      Hamamatu, Shizuoka, Japan
  • 1987–2001
    • Kanazawa University
      • School of Medicine
      Kanazawa, Ishikawa, Japan
  • 1996
    • National Research Institute for Child Health and Development, Tokyo
      Edo, Tōkyō, Japan
  • 1992
    • Seirei Hamamatsu General Hospital
      Hamamatu, Shizuoka, Japan
  • 1989–1990
    • Kanazawa Medical University
      • Department of Surgery II
      Kanazawa-shi, Ishikawa-ken, Japan