Browsing by Subject "Liver Neoplasms"
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Item The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-02) Jinjuvadia, Raxitkumar; Patel, Suhag; Liangpunsakul, Suthat; Department of Medicine, IU School of MedicineBACKGROUND: The metabolic syndrome (MetS) and/or its individual components have been linked to the development of cancer. Recent studies have suggested a similar link to hepatocellular carcinoma (HCC). The aim of this study was to evaluate the direction and magnitude of the association between the MetS and HCC. METHODS: Two reviewers independently conducted a systemic search to identify the available evidence from databases from January 1980 to June 2012. Search terms included "Metabolic syndrome," "insulin resistance syndrome," "metabolic abnormalities" combined with "hepatocellular carcinoma," and "liver cancer." No language restriction was applied to the search. Only studies reporting an effect measure for the association between MetS and HCC were eligible for inclusion. Publication bias was assessed using the Begg and Egger tests, with a visual inspection of funnel plot. All analyses were performed using Comprehensive Meta-analysis version 2 software. RESULTS: Four studies (3 cohort and 1 case control) with a total of 829,651 participants were included in the analysis. The age range of participants was between 30 and 84 years. The combined analysis showed an overall 81% increased risk of HCC in cases with MetS (relative risk, 1.81; 95% confidence interval, 1.37-2.41). After excluding the single case-control study from analysis, the overall risk ratio remained statistically significant (relative risk, 1.49; 95% confidence interval, 1.27-1.74). Funnel plot inspection, Begg and Egger tests showed no evidence of publication bias for combined analysis. CONCLUSIONS: Though studies are scarce, currently available epidemiologic data are suggestive of significantly higher risk of HCC among patients with MetS.Item Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap(Nature Research, 2018-11-23) Lee, Youngmin A.; Noon, Luke A.; Akat, Kemal M.; Ybanez, Maria D.; Lee, Ting-Fang; Berres, Marie-Luise; Fujiwara, Naoto; Goossens, Nicolas; Chou, Hsin-I; Parvin-Nejad, Fatemeh P.; Khambu, Bilon; Kramer, Elisabeth G.M.; Gordon, Ronald; Pfleger, Cathie; Germain, Doris; John, Gareth R.; Campbell, Kirk N.; Yue, Zhenyu; Yin, Xiao-Ming; Cuervo, Ana Maria; Czaja, Mark J.; Fiel, M. Isabel; Hoshida, Yujin; Friedman, Scott L.; Pathology and Laboratory Medicine, School of MedicineActivation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.Item Decreased PCSK9 expression in human hepatocellular carcinoma(Springer (Biomed Central Ltd.), 2015-12-16) Bhat, Mamatha; Skill, Nicolas; Marcus, Victoria; Deschenes, Marc; Tan, Xianming; Bouteaud, Jeanne; Negi, Sarita; Awan, Zuhier; Aikin, Reid; Kwan, Janet; Amre, Ramila; Tabaries, Sebastien; Hassanain, Mazen; Seidah, Nabil G.; Maluccio, Mary; Siegel, Peter; Metrakos, Peter; Department of Surgery, IU School of MedicineBACKGROUND: The management of hepatocellular carcinoma (HCC) is limited by the lack of adequate screening biomarkers and chemotherapy. In response, there has been much interest in tumor metabolism as a therapeutic target. PCSK9 stimulates internalization of the LDL-receptor, decreases cholesterol uptake into hepatocytes and affects liver regeneration. Thus, we investigated whether PCSK9 expression is altered in HCC, influencing its ability to harness cholesterol metabolism. METHODS: Thirty-nine patients undergoing partial hepatectomy or liver transplantation for HCC were consented for use of HCC tissue to construct a tissue microarray (TMA). The TMA was immunostained for PCSK9. Imagescope software was used to objectively determine staining, and assess for pathological and clinical correlations. PCSK9 and LDL receptor mRNA levels in flash-frozen HCC and adjacent liver tissue were determined by quantitative RT-PCR. Serum PCSK9 levels were determined by ELISA. RESULTS: By immunohistochemistry, there was significantly lower expression of PCSK9 in HCC as compared to adjacent cirrhosis (p-value < 0.0001, wilcoxon signed-rank test). Significantly greater staining of PCSK9 was present in cirrhosis compared to HCC (p value <0.0001), and positivity (percentage of positive cells) was significantly greater in cirrhosis compared to HCC (p-value < 0.0001). Conversely, significantly higher expression of LDL-R was present in HCC as compared to the adjacent cirrhosis (p-value < 0.0001). There was no significant correlation of PCSK9 staining with grade of tumor, but there were significant correlations between PCSK9 staining and stage of fibrosis, according to spearman correlation test. PCSK9 mRNA levels were relatively less abundant within HCC compared to adjacent liver tissue (p-value =0.08) and normal control tissue (p-value =0.02). In contrast, serum PCSK9 levels were significantly increased among patients with HCC compared to those with chronic liver disease without HCC (p-value =0.029). LDL receptor mRNA was consistantly greater in HCC when compared to normal control tissue (p-value = 0.06) and, in general, was significantly greater in HCC when compared to adjacent liver (p-value = 0.04). CONCLUSIONS: The decreased expression of PCSK9 and conversely increased LDL-R expression in HCC suggests that HCC modulates its local microenvironment to enable a constant energy supply. Larger-scale studies should be conducted to determine whether PCSK9 could be a therapeutic target for HCC.Item Detection of Hepatocellular Carcinoma in Hepatitis C Patients: Biomarker Discovery by LC-MS(Elsevier, 2014-09-01) Bowers, Jeremiah; Hughes, Emma; Skill, Nicholas; Maluccio, Mary; Raftery, Daniel; Department of Surgery, IU School of MedicineHepatocellular carcinoma (HCC) accounts for most cases of liver cancer worldwide; contraction of hepatitis C (HCV) is considered a major risk factor for liver cancer even when individuals have not developed formal cirrhosis. Global, untargeted metabolic profiling methods were applied to serum samples from patients with either HCV alone or HCC (with underlying HCV). The main objective of the study was to identify metabolite based biomarkers associated with cancer risk, with the long term goal of ultimately improving early detection and prognosis. Serum global metabolite profiles from patients with HCC (n=37) and HCV (n=21) were obtained using high performance liquid chromatography-mass spectrometry (HPLC-MS) methods. The selection of statistically significant metabolites for partial least-squares discriminant analysis (PLS-DA) model creation based on biological and statistical significance was contrasted to that of a traditional approach utilizing p-values alone. A PLS-DA model created using the former approach resulted in a model with 92% sensitivity, 95% specificity, and an AUROC of 0.93. A series of PLS-DA models iteratively utilizing three to seven metabolites that were altered significantly (p<0.05) and sufficiently (FC≤0.7 or FC≥1.3) showed the best performance using p-values alone, the PLS-DA model was capable of generating 73% sensitivity, 95% specificity, and an AUROC of 0.92. Metabolic profiles derived from LC-MS readily distinguish patients with HCC and HCV from those with HCV only. Differences in the metabolic profiles between highrisk individuals and HCC indicate the possibility of identifying the early development of liver cancer in at risk patients. The use of biological significance as a selection process prior to PLSDA modeling may offer improved probabilities for translation of newly discovered biomarkers to clinical application.Item Epithelial Splicing Regulatory Protein 1 is a Favorable Prognostic Factor in Pancreatic Cancer that Attenuates Pancreatic Metastases(Nature Publishing Group, 2014-09-04) Ueda, Junji; Matsuda, Yoko; Yamahatsu, Kazuya; Uchida, Eiji; Naito, Zenya; Korc, Murray; Ishiwata, Toshiyuki; Department of Medicine, IU School of MedicineEpithelial splicing regulatory protein 1 (ESRP1) binds the FGFR-2 auxiliary cis-element ISE/ISS-3, located in the intron between exon IIIb and IIIc, and primarily promotes FGFR-2 IIIb expression. Here we assessed the role of ESRP1 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis was performed using anti-ESRP1, FGFR-2 IIIb and FGFR-2 IIIc antibodies in 123 PDAC cases. ESRP1-expression vector and small interference RNA (siRNA) targeting ESRP1 were transfected into human PDAC cells, and cell growth, migration and invasion were analyzed. In vivo heterotopic and orthotopic implantations using ESRP1 overexpression clones were performed and effects on pancreatic tumor volumes and hepatic and pulmonary metastases determined. ESRP1 immunoreactivity was strong in the nuclei of cancer cells in well-to-moderately differentiated PDACs, but weak in poorly-differentiated cancers. Well-to-moderately differentiated cancers also exhibited high FGFR-2 IIIb and low FGFR-2 IIIc expression, whereas this ratio was reversed in the poorly-differentiated cancers. Increased ESRP1 expression was associated with longer survival by comparison with low-ESRP1 expression, and PANC-1 cells engineered to express ESRP1 exhibited increased FGFR-2 IIIb expression and decreased migration and invasion in vitro, whereas ESRP1 siRNA-transfected KLM-1 cells exhibited increased FGFR-2 IIIc expression and increased cell growth, migration and invasion. In vivo, ESRP1-overexpressing clones formed significantly fewer liver metastases as compared with control clones. ESRP1 regulates the expression pattern of FGFR-2 isoforms, attenuates cell growth, migration, invasion, and metastasis, and is a favorable prognostic factor in PDAC. Therefore, devising mechanisms to up-regulate ESRP1 may exert a beneficial therapeutic effect in PDAC.Item HRD1 attenuates the high uptake of [18F]FDG in hepatocellular carcinoma PET imaging(Elsevier, 2021-05) Li, Ai-Mei; Lin, Xia-Wen; Shen, Jing-Tao; Li, Min; Zheng, Qi-Huang; Zhou, Zheng-Yang; Shi, Ming; Radiology and Imaging Sciences, School of MedicineINTRODUCTION: Due to individual deviations in tumor tissue uptake, the role of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) in hepatocellular carcinoma (HCC) diagnosis is limited. β-Hydroxy β-methylglutaryl-CoA reductase degradation 1 (HRD1) plays a key role in clearing misfolded proteins. This study is aimed to investigate the role and mechanism of HRD1 in [18F]FDG uptake for the diagnosis of HCC. METHODS: HRD1 expression level was detected using immunohistochemical (IHC) staining in 9 HCC patients. [18F]FDG PET/CT scans were conducted before treatment. [18F]FDG uptakes in HRD1 overexpressed and knockdown transgenic models were measured by γ-counter and microPET imaging. The GLUT1-HRD1 complex was examined by co-immunoprecipitation and IHC assays. GLUT1 expression in different cell lines, xenograft models and HCC patients was evaluated by Western blot and IHC assays. RESULTS: HRD1 was highly expressed in the HCC tumors of patients with low [18F]FDG uptake, while the HRD1 expression was obviously low in the higher [18F]FDG uptake group. Both in vitro and in vivo studies found that HRD1 significantly inhibited [18F]FDG uptake in HCC Huh7 cell lines and animal models. Furthermore, the co-location and interaction of HRD1 with GLUT1 were detected, and the results also indicate that HRD1 could induce the degradation of GLUT1 in vitro and in vivo. CONCLUSION: HRD1 inhibits the high uptake of [18F]FDG in HCC tumor cells by inducing degradation of GLUT1, which leads to decreased diagnostic efficiency of [18F]FDG PET imaging for HCC. ADVANCES IN KNOWLEDGE: This study suggests that HRD1 inhibits the high uptake of [18F]FDG in HCC tumor by inducing degradation of GLUT1. IMPLICATIONS FOR PATIENT CARE: HCC diagnosis with [18F]FDG PET should be accompanied by determination of HRD1 expression, and patients with high tumor HRD1 expression might be unsuitable for [18F]FDG PET.Item Inflammatory Chemokines MIP-1δ and MIP-3α Are Involved in the Migration of Multipotent Mesenchymal Stromal Cells Induced by Hepatoma Cells(Mary Ann Liebert, Inc., 2015-05-15) Lejmi, Esma; Perriraz, Nadja; Clement, Sophie; Morel, Philippe; Baertschiger, Reto; Christofilopoulos, Panayiotis; Meier, Raphael; Bosco, Domenico; Gonelle-Gispert, Carmen; Buhler, Leo H.; Department of Surgery, IU School of MedicineIn vivo, bone marrow-derived multipotent mesenchymal stromal cells (MSC) have been identified at sites of tumors, suggesting that specific signals mobilize and activate MSC to migrate to areas surrounding tumors. The signals and migratory mechanisms that guide MSC are not well understood. Here, we investigated the migration of human MSC induced by conditioned medium of Huh-7 hepatoma cells (Huh-7 CM). Using a transwell migration system, we showed that human MSC migration was increased in the presence of Huh-7 CM. Using a human cytokine antibody array, we detected increased levels of MIP-1δ and MIP-3α in Huh-7 CM. Recombinant chemokines MIP-1δ and MIP-3α induced MSC migration. Anti-MIP-1δ and anti-MIP-3α antibodies added to Huh-7 CM decreased MSC migration, further suggesting that MIP-1δ and MIP-3α were implicated in the Huh-7 CM-induced MSC migration. By real-time polymerase chain reaction, we observed an absence of chemokine receptors CCR2 and CXCR2 and low expression of CCR1, CCR5, and CCR6 in MSC. Expression of these chemokine receptors was not regulated by Huh-7 CM. Furthermore, matrix metalloproteinase 1 (MMP-1) expression was strongly increased in MSC after incubation with Huh-7 CM, suggesting that MSC migration depends on MMP-1 activity. The signaling pathway MAPK/ERK was activated by Huh-7 CM but its inhibition by PD98059 did not impair Huh-7 CM-induced MSC migration. Further, long-term incubation of MSC with MIP-1δ increased α-smooth muscle actin expression, suggesting its implication in the Huh-7 CM-induced evolvement of MSC into myofibroblasts. In conclusion, we report that two inflammatory cytokines, MIP-1δ and MIP-3α, are able to increase MSC migration in vitro. These cytokines might be responsible for migration and evolvement of MSC into myofibroblasts around tumors.