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1.
Hepatology ; 75(4): 997-1011, 2022 04.
Article in English | MEDLINE | ID: mdl-34478159

ABSTRACT

BACKGROUND AND AIMS: Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV-infected iCCA (HBV-iCCA) tumors. APPROACH AND RESULTS: We profiled a cohort of 108 HBV-iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV-infected HCC (HBV-HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV-cHCC/CCA; n = 59), and conventional (n = 154) and fluke-related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial-mesenchymal transition-related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non-protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV-iCCA was closer to that of nonviral conventional iCCA, than to HBV-HCC and HBV-cHCC/CCA. CONCLUSIONS: Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.


Subject(s)
Bile Duct Neoplasms , Carcinoma, Hepatocellular , Cholangiocarcinoma , Liver Neoplasms , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Carcinogenesis , Carcinoma, Hepatocellular/pathology , Cholangiocarcinoma/genetics , Cholangiocarcinoma/pathology , Genomics , Hepatitis B virus/genetics , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Virus Integration/genetics
2.
Cell Mol Life Sci ; 76(13): 2647-2662, 2019 Jul.
Article in English | MEDLINE | ID: mdl-30903204

ABSTRACT

Hepatitis B virus (HBV) X protein (HBx) is associated with hepatocarcinogenesis. E2-EPF ubiquitin carrier protein (UCP) catalyzes ubiquitination of itself and von Hippel-Lindau protein (pVHL) for degradation and associates with tumor growth and metastasis. However, it remains unknown whether HBx modulates the enzyme activity of UCP and thereby influences hepatocarcinogenesis. Here, we show that UCP is highly expressed in liver tissues of HBx-transgenic mice, but not non-transgenic mice. UCP was more frequently expressed in HBV-positive liver cancers than in HBV-negative liver cancers. HBx binds to UCP specifically and serotype independently, and forms a ternary complex with UCP and pVHL. HBx inhibits self-ubiquitination of UCP, but enhances UCP-mediated pVHL ubiquitination, resulting in stabilization of hypoxia-inducible factor-1α and -2α. HBx and UCP stabilize each other by mutually inhibiting their ubiquitination. HBx promotes cellular proliferation and metastasis via UCP. Our findings suggest that UCP plays a key role in HBV-related hepatocarcinogenesis.


Subject(s)
Carcinoma, Hepatocellular/secondary , Hepatitis B/complications , Liver Neoplasms/pathology , Trans-Activators/metabolism , Ubiquitin-Conjugating Enzymes/chemistry , Animals , Apoptosis , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/virology , Cell Proliferation , Disease Progression , Female , Hepatitis B/virology , Hepatitis B virus/isolation & purification , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/virology , Mice , Mice, Inbred BALB C , Mice, Nude , Mice, Transgenic , Protein Stability , Signal Transduction , Trans-Activators/genetics , Tumor Cells, Cultured , Ubiquitin-Conjugating Enzymes/genetics , Ubiquitin-Conjugating Enzymes/metabolism , Ubiquitination , Viral Regulatory and Accessory Proteins , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Xenograft Model Antitumor Assays
3.
Exp Mol Med ; 50(4): 1-10, 2018 04 06.
Article in English | MEDLINE | ID: mdl-29622769

ABSTRACT

Altered expression of suppressor of cytokine signaling (SOCS) is found in various tumors. However, regulation of SOCS2 by upstream molecules has yet to be clearly elucidated, particularly in tumor cells. SCOCS2 expression was examined in tumor cells transfected with an inducible p53 expression system. The impact of SOCS2 on cell proliferation was measured with in vitro assays. Inhibition of tumorigenicity by SOCS2 knockdown was assessed via a mouse model. Expression profiles were compared and genes differentially expressed were identified using four types of p53-null cells (Saos, HLK3, PC3, and H1299) and the same cells stably expressing p53. Twelve kinds of target genes were simultaneously upregulated or downregulated by p53 in three or more sets of p53-null cells. SOCS2 expression was reciprocally inhibited by inducible p53 expression in p53-null cells, even colon cancer cells. SOCS2 promoter activity was inhibited by wild type but not mutant p53. SOCS2 knockdown inhibited tumor growth in vitro and in an animal xenograph model. SOCS2 overexpression was detected in a murine model of azoxymethane/dextran sulfate sodium-induced colitis-associated colon cancer compared to mock-treated controls. SOCS2 expression was heterogeneously upregulated in some human colon cancers. Thus, SOCS2 was upregulated by p53 dysfunction and seemed to be associated with the tumorigenic potential of colon cancer.


Subject(s)
Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Suppressor of Cytokine Signaling Proteins/genetics , Tumor Suppressor Protein p53/genetics , Animals , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Colonic Neoplasms/pathology , Female , Gene Expression Profiling , Gene Knockdown Techniques , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , Mice , Suppressor of Cytokine Signaling Proteins/metabolism , Transcriptome , Tumor Suppressor Protein p53/metabolism
4.
Cancer Sci ; 108(11): 2176-2186, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28859238

ABSTRACT

Lipocalin 2 (LCN2), a member of the lipocalin superfamily, plays an important role in oncogenesis and progression in various types of cancer. However, the expression pattern and functional role of LCN2 in colorectal cancer (CRC) is still poorly understood. The purpose of the present study was to investigate whether LCN2 is associated with proliferation and the epithelial-mesenchymal transition (EMT) in CRC and to elucidate the underlying signaling pathways. LCN2 was preferentially expressed in CRC cells compared to normal tissues. However, LCN2 expression was significantly lower in metastatic or advanced-stage CRC than in non-metastatic or early stage CRC. Knockdown of LCN2 using small interfering RNA (siRNA) in CRC cells expressing a high level of LCN2 induced cell proliferation and a morphological switch from an epithelial to mesenchymal state. Furthermore, downregulation of LCN2 in CRC cells increased cell migration and invasion involved in the regulation of EMT markers. Knockdown of LCN2 also induced glucose consumption and lactate production, accompanied by an increase in energy metabolism-related genes. Taken together, our findings indicated that LCN2 negatively modulated proliferation, EMT and energy metabolism in CRC cells. Accordingly, LCN2 may be a candidate metastasis suppressor and potential therapeutic target in CRC.


Subject(s)
Cell Proliferation/genetics , Colorectal Neoplasms/genetics , Energy Metabolism/genetics , Epithelial-Mesenchymal Transition/genetics , Lipocalin-2/genetics , Aged , Cell Line, Tumor , Cell Movement/genetics , Colorectal Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Glucose/metabolism , Humans , Male , Signal Transduction
5.
Oncotarget ; 8(11): 18129-18144, 2017 Mar 14.
Article in English | MEDLINE | ID: mdl-28184024

ABSTRACT

Opa interacting protein 5 (OIP5) is upregulated in some types of human cancers, but the biological implications of its upregulation have not yet been clarified in human hepatocellular carcinoma (HCC). In this study, the signaling pathway downstream of OIP5 was analyzed by proteome kinase profiling. A putative microRNA targeting OIP5 was identified using a miRNA PCR array. Tumorigenicity and metastatic ability were examined in an orthotopic animal model. OIP5 expression was strongly detected in early and advanced tumors via gene expression profiling and immunohistochemical staining analyses. Cells with knockdown of OIP5 via target shRNA exhibited reduced hepatic mass formation and metastatic tumor nodules in an orthotopic mouse model. OIP5-induced AKT activation was mediated by both mTORC2 and p38/PTEN activation. AKT activation was linked to mTORC1 and GSK-3ß/ß-catenin signaling, which are primarily associated with tumor cell growth and metastasis, respectively. miR-15b-5p, which targets OIP5, efficiently inhibited OIP5-mediated mTORC1 and GSK-3ß/ß-catenin signaling. These findings suggest that OIP5 may be involved in HCC growth and metastasis and that miR-15b-5p inhibits OIP5-mediated oncogenic signaling in HCC.


Subject(s)
Carcinoma, Hepatocellular/pathology , Chromosomal Proteins, Non-Histone/metabolism , Gene Expression Regulation, Neoplastic/genetics , Liver Neoplasms/pathology , MicroRNAs/metabolism , Animals , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Cycle Proteins , Cell Line, Tumor , Chromosomal Proteins, Non-Histone/genetics , Flow Cytometry , Fluorescent Antibody Technique , Gene Expression Profiling , Gene Knockdown Techniques , Humans , Immunoblotting , Immunohistochemistry , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Mechanistic Target of Rapamycin Complex 1 , Mice , MicroRNAs/genetics , Multiprotein Complexes/metabolism , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Polymerase Chain Reaction , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolism , Transcriptome , Xenograft Model Antitumor Assays , beta Catenin/metabolism
6.
World J Gastroenterol ; 23(2): 297-305, 2017 Jan 14.
Article in English | MEDLINE | ID: mdl-28127203

ABSTRACT

AIM: To assess the effect of long-term oral nucleos(t)ide analogues (NUCs) therapy on liver volume change in patients with suppress hepatitis B virus (HBV)-related liver cirrhosis. METHODS: We reviewed the data of naïve patients with HBV-related liver cirrhosis, who had taken oral NUCs therapy, between 2003 and 2007 at Chonbuk University Hospital. We analyzed two consecutive sets of abdominal computerized tomography scans-one at the time of treatment initiation and another at the second-year follow-up. Liver volume was calculated by 3-dimensional liver extraction volumetry program. RESULTS: A total of 55 patients (34 males) were included. There was 114.3 mL ± 167.8 mL (12.9% ± 17.9%) of increase in liver volume during the two years of NUCs therapy (993.8 mL ± 242.8 mL at baseline vs 1108.1 mL ± 263.3 mL at two-year follow-up, P < 0.001). The ratio of the measured baseline liver volume to the estimated standard liver volume was improved from 70.8% to 78.0%. An increase in liver volume was shown not only in patients with compensated cirrhosis (P = 0.046) but also in those with decompensated cirrhosis (P < 0.001). Significant factors for volume increases were Child-Turcotte-Pugh grade and model for end-stage liver disease score improvement without virological breakthrough. In multiple linear regression analysis, delta albumin and delta alanine aminotransferase levels showed a significant association with the increase in liver volume (P = 0.002 and 0.005, respectively). CONCLUSION: Long-term oral NUCs therapy in patients with HBV-related liver cirrhosis lead to significant increase in liver volume assessed with 3-dimensional liver extraction volumetry program.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis B virus/isolation & purification , Liver Cirrhosis/drug therapy , Liver Regeneration/drug effects , Liver/pathology , Nucleosides/analysis , Nucleotides/analysis , Administration, Oral , Adult , Alanine Transaminase/blood , Antiviral Agents/administration & dosage , End Stage Liver Disease/diagnosis , Female , Follow-Up Studies , Humans , Imaging, Three-Dimensional/methods , Liver/diagnostic imaging , Liver/virology , Liver Cirrhosis/blood , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/virology , Long-Term Care , Male , Middle Aged , Nucleosides/administration & dosage , Nucleosides/therapeutic use , Nucleotides/administration & dosage , Nucleotides/therapeutic use , Organ Size/drug effects , Retrospective Studies , Serum Albumin/analysis , Severity of Illness Index , Tomography, X-Ray Computed , Treatment Outcome , Viral Load/drug effects
7.
Exp Mol Med ; 48(12): e275, 2016 12 02.
Article in English | MEDLINE | ID: mdl-27909336

ABSTRACT

C-terminal-truncated hepatitis B virus (HBV) X (HBx) (ctHBX) is frequently detected in hepatocellular carcinoma (HCC) through HBV integration into the host genome. However, the molecular mechanisms underlying ctHBx-associated oncogenic signaling have not yet been clarified. To elucidate the biological role of ctHBx in hepato-oncogenesis, we functionally analyzed ctHBx-mediated regulation of the activin membrane-bound inhibitor bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) through transforming growth factor-ß (TGF-ß) or ß-catenin (CTNNB1) in HCC cells and in an animal model, and we compared its role to that of the full-length HBx protein. Ectopic ctHBx expression generated more colonies in anchorage-dependent and -independent growth assays than did HBx expression alone. ctHBx downregulated BAMBI to a greater degree than did HBx in HCC cells. HBx activated the Wnt/ß-catenin pathway, which positively regulated the BAMBI expression through T-cell factor 1 signaling, whereas ctHBx negatively regulated the Wnt/ß-catenin pathway. BAMBI downregulated the ß-catenin and TGF-ß1 signaling pathways. TGF-ß1 positively regulated BAMBI expression thorough Smad3 signaling. Furthermore, knockdown of BAMBI was more tumorigenic in HCC cells. Therefore, downregulation of both ß-catenin and TGF-ß1 signaling by BAMBI might contribute to tumor suppression in mice xenotransplanted with HepG2 or SH-J1 cells. Taken together, ctHBx may have a more oncogenic role than HBx through its inhibition of tumor-suppressive ß-catenin/BAMBI signaling.


Subject(s)
Hepatitis B virus/physiology , Hepatitis B/complications , Liver Neoplasms/virology , Membrane Proteins/metabolism , Signal Transduction , Trans-Activators/metabolism , beta Catenin/metabolism , Animals , Hep G2 Cells , Hepatitis B/metabolism , Hepatitis B/pathology , Hepatitis B/virology , Humans , Liver/metabolism , Liver/pathology , Liver/virology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Mice , Viral Regulatory and Accessory Proteins , Wnt Signaling Pathway
8.
Exp Mol Pathol ; 101(1): 150-6, 2016 08.
Article in English | MEDLINE | ID: mdl-27460275

ABSTRACT

Genome-wide association study in diffusely infiltrating type cholangiocarcinoma (CC) can be limited due to the difficulty of obtaining tumor tissue. We aimed to evaluate the genomic alterations of diffusely infiltrating type CC using next-generation sequencing (NGS) of bile and to compare the variations with those of mass-forming type CC. A total of 24 bile samples obtained during endoscopic retrograde cholangiopancreatography (ERCP) and 17 surgically obtained tumor tissue samples were evaluated. Buffy coat and normal tissue samples were used as controls for a somatic mutation analysis. After extraction of genomic DNA, NGS analysis was performed for 48 cancer related genes. There were 27 men and 14 women with a mean age of 65.0±11.8years. The amount of extracted genomic DNA from 3cm(3) of bile was 66.0±84.7µg and revealed a high depth of sequencing coverage. All of the patients had genomic variations, with an average number of 19.4±2.8 and 22.3±3.3 alterations per patient from the bile and tumor tissue, respectively. After filtering process, damaging SNPs (8 sites for each type of CC) were predicted by analyzing tools, and their target genes showed relevant differences between the diffusely infiltrating and mass-forming type CC. Finally, in somatic mutation analysis, tumor-normal paired 14 tissue and 6 bile samples were analyzed, genomic alterations of EGFR, FGFR1, ABL1, PIK3CA, and CDKN2A gene were seen in the diffusely infiltrating type CC, and TP53, KRAS, APC, GNA11, ERBB4, ATM, SMAD4, BRAF, and IDH1 were altered in the mass-forming type CC group. STK11, GNAQ, RB1, KDR, and SMO genes were revealed in both groups. The NGS analysis was feasible with bile sample and diffusely infiltrating type CC revealed genetic differences compared with mass-forming type CC. Genome-wide association study could be performed using bile sample in the patients with CC undergoing ERCP and a different genetic approach for accurate diagnosis, pathogenesis study, and targeted therapy will be needed in diffusely infiltrating type CC.


Subject(s)
Bile/metabolism , Cholangiocarcinoma/genetics , Genes, Neoplasm , High-Throughput Nucleotide Sequencing/methods , Adult , Aged , Aged, 80 and over , DNA, Neoplasm/analysis , Female , Humans , Male , Middle Aged , Mutation/genetics , Polymorphism, Single Nucleotide/genetics , Software
9.
Clin Cancer Res ; 22(5): 1256-64, 2016 Mar 01.
Article in English | MEDLINE | ID: mdl-26459179

ABSTRACT

PURPOSE: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. EXPERIMENTAL DESIGN: We analyzed gene expression data from Mst1/2(-/-) and Sav1(-/-) mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. RESULTS: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12-2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001). CONCLUSIONS: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis.


Subject(s)
Adaptor Proteins, Signal Transducing/biosynthesis , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Phosphoproteins/biosynthesis , Adaptor Proteins, Signal Transducing/genetics , Adult , Aged , Aged, 80 and over , Animals , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic , Hippo Signaling Pathway , Humans , Intracellular Signaling Peptides and Proteins/biosynthesis , Intracellular Signaling Peptides and Proteins/genetics , Kaplan-Meier Estimate , Liver Neoplasms/pathology , Male , Mice , Middle Aged , Phosphoproteins/genetics , Prognosis , Protein Serine-Threonine Kinases/biosynthesis , Protein Serine-Threonine Kinases/genetics , Signal Transduction , Trans-Activators , Transcription Factors , Transcriptional Coactivator with PDZ-Binding Motif Proteins , YAP-Signaling Proteins
10.
J Gastroenterol Hepatol ; 31(6): 1220-8, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26574150

ABSTRACT

BACKGROUND AND AIM: Epithelial-mesenchymal transition (EMT) of biliary epithelial cells (BECs) plays an important role in biliary fibrosis. This study investigated the effects of simvastatin on the lipopolysaccharide (LPS)-induced EMT and related signal pathways in BECs. METHODS: Biliary epithelial cells were exposed to LPS (2 µg/mL) or transforming growth factor ß1 (TGF-ß1) (5 ng/mL) for 5 days. The EMT was assessed by a gain of mesenchymal cell markers (vimentin, N-cadherin, slug, and Twist-1) and a loss of epithelial cell markers (E-cadherin). The effects of simvastatin on the EMT induced by LPS or TGF-ß1 were determined by the changes in the levels of EMT markers and TLR4 and in the c-Jun N-terminal kinase (JNK), p38, and nuclear factor-κB (NF-κB) signaling pathways. RESULTS: Compared with the BECs treated with LPS alone, co-treatment with simvastatin and LPS induced an increase in the expression of E-cadherin and decreases in the expression levels of mesenchymal cell markers. The LPS-induced TLR4 expression level was slightly decreased by co-treatment with simvastatin. LPS-induced BEC growth was markedly inhibited by co-treatment with simvastatin. Furthermore, pretreatment with simvastatin inhibited the LPS-induced EMT in BECs by downregulating NF-κB and JNK phosphorylation. The suppressive effects of simvastatin pretreatment on the induction of the EMT by TGF-ß1 were also demonstrated in H69 cells. CONCLUSIONS: Our results demonstrate that LPS or TGF-ß1 promote the EMT in BECs that that pretreatment with simvastatin inhibited the induced EMT by downregulating toll-like receptor 4 and NF-κB phosphorylation. This finding suggests that simvastatin can be considered a new agent for preventing biliary fibrosis associated with the EMT of BECs.


Subject(s)
Bile Ducts/drug effects , Epithelial Cells/drug effects , Epithelial-Mesenchymal Transition/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Lipopolysaccharides/toxicity , Liver Cirrhosis, Biliary/prevention & control , NF-kappa B/metabolism , Simvastatin/pharmacology , Toll-Like Receptor 4/metabolism , Bile Ducts/metabolism , Bile Ducts/pathology , Biomarkers/metabolism , Cell Line, Transformed , Cell Proliferation/drug effects , Cytoprotection , Down-Regulation , Epithelial Cells/metabolism , Epithelial Cells/pathology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Liver Cirrhosis, Biliary/chemically induced , Liver Cirrhosis, Biliary/metabolism , Liver Cirrhosis, Biliary/pathology , Phosphorylation , Signal Transduction/drug effects , Time Factors , Toll-Like Receptor 4/genetics , Transforming Growth Factor beta1/toxicity
11.
Oncol Lett ; 9(5): 2135-2142, 2015 May.
Article in English | MEDLINE | ID: mdl-26137027

ABSTRACT

Recently, the nuclear factor (NF)-κB inhibitor parthenolide (PT) was identified as a promising anticancer agent for the promotion of cancer cell apoptosis. Additionally, our previous study demonstrated that PT administration suppresses tumor growth in a xenograft model of colorectal cancer cells via regulation of the B-cell lymphoma-2 (Bcl-2) family. However, the role of PT in the development of colitis-associated colon cancer (CAC) is poorly understood. Therefore, the aim of the present study was to investigate the effects of PT administration on CAC using a murine model. Azoxymethane (AOM) and dextran sulfate sodium (DSS) were administered to induce experimental CAC in the following three groups of treated mice: i) AOM and DSS plus vehicle; ii) AOM, DSS and 2 mg/kg PT; and iii) AOM, DSS and 4 mg/kg PT. It was demonstrated that the histological acuteness of AOM/DSS-induced CAC was significantly reduced following the administration of PT, resulting in decreased NF-κB p65 expression levels via a blockade of phosphorylation and subsequent degradation of inhibitor of κB-α (IκBα). Furthermore, PT administration appeared to enhance the process of carcinogenesis via the downregulation of the antiapoptotic proteins Bcl-2 and Bcl-extra large, mediated by inhibition of NF-κB activation. Apoptosis and caspase-3 expression were markedly increased in the PT-treated group. These findings indicate that PT inhibits IκBα phosphorylation and NF-κB activation, resulting in the initiation of apoptosis and the eventual suppression of CAC development. The beneficial effects of PT treatment observed in the experimental CAC model indicate the potential chemopreventive and therapeutic role of PT in CAC.

12.
Sci Rep ; 5: 10897, 2015 Jun 03.
Article in English | MEDLINE | ID: mdl-26039737

ABSTRACT

We validated a single-stranded, DNA aptamer-based, diagnostic method capable of detecting Lipocalin-2 (LCN2), a biomarker from clinically relevant hepatocellular carcinoma (HCC) patient serum, in the sandwich assay format. Nine aptamers (LCN2_apta1 to LCN2_apta9) for LCN2 were screened with SELEX processes, and a sandwich pair (LCN2_apta2 and LCN2_apta4) was finally chosen using surface plasmon resonance (SPR) and dot blotting analysis. The result of the proposed aptamer sandwich construction shows that LCN2 was sensitively detected in the concentration range of 2.5-500 ng mL(-1) with a limit of detection of 0.6 ng mL(-1). Quantitative measurement tests in HCC patients were run on straight serum and were compared with the performance of the conventional antibody-based ELISA kit. The aptamer sandwich assay demonstrated an excellent dynamic range for LCN2 at clinically relevant serum levels, covering sub-nanogram per mL concentrations. The new approach offers a simple and robust method for detecting serum biomarkers that have low and moderate abundance. It consists of functionalization, hybridization and signal read-out, and no dilution is required. The results of the study demonstrate the capability of the aptamer sandwich assay platform for diagnosing HCC and its potential applicability to the point-of-care testing (POCT) system.


Subject(s)
Aptamers, Nucleotide , Carcinoma, Hepatocellular/blood , Lipocalins/blood , Liver Neoplasms/blood , Molecular Diagnostic Techniques , Proto-Oncogene Proteins/blood , Acute-Phase Proteins , Adult , Aged , Carcinoma, Hepatocellular/diagnosis , Female , Humans , Lipocalin-2 , Liver Neoplasms/diagnosis , Male , Middle Aged , Reproducibility of Results , SELEX Aptamer Technique , Sensitivity and Specificity , Surface Plasmon Resonance/methods
13.
J Korean Med Sci ; 30(5): 598-605, 2015 May.
Article in English | MEDLINE | ID: mdl-25931791

ABSTRACT

Bacterial infection is an important cause of death in patients with liver cirrhosis. The aim of this study was to investigate the clinical characteristics and prognostic impact of bacterial infection in hospitalized patients with alcoholic liver disease (ALD). We retrospectively analyzed data from 409 patients consecutively admitted to a tertiary referral center with ALD diagnosis. Of a total of 544 admissions, 133 (24.4%) cases presented with bacterial infection, of which 116 were community-acquired whereas 17 were hospital-acquired. The common types of infection were pneumonia (38%), biliary tract infection (17%), soft tissue infection (12%), and spontaneous bacterial peritonitis (9%). Diabetes, serum Na <135 mM/L, albumin <2.5 g/dL, C-reactive protein ≥20 mg/L, systemic inflammatory response syndrome (SIRS) positivity were independently associated with bacterial infection in patients with ALD. Overall 30-day and 90-day mortalities in patients with bacterial infection were significantly (P < 0.001) higher than those without infection (22.3% vs. 5.1% and 32.3% vs. 8.2%, respectively). Furthermore, bacterial infection (HR, 2.2; 95% CI, 1.049-4.579, P = 0.037), SIRS positivity (HR, 2.5; 95% CI, 1.240-4.861, P = 0.010), Maddrey's discriminant function score ≥32 (HR, 2.3; 95% CI, 1.036-5.222, P = 0.041), and hemoglobin <12 g/dL (HR, 2.4; 95% CI, 1.081-5.450, P = 0.032) were independent predictors of short-term mortality. In conclusion, bacterial infection and SIRS positivity predicted short-term prognosis in hospitalized patients with ALD. A thorough evaluation at admission or on clinical deterioration is required to detect possible infection with prompt management.


Subject(s)
Bacterial Infections/diagnosis , Liver Diseases, Alcoholic/diagnosis , Adult , Aged , Bacterial Infections/complications , Bacterial Infections/mortality , C-Reactive Protein/analysis , Candida/isolation & purification , Female , Gram-Negative Bacteria/isolation & purification , Gram-Positive Bacteria/isolation & purification , Hemoglobins/analysis , Hospitalization , Humans , Linear Models , Liver Diseases, Alcoholic/complications , Male , Middle Aged , Patients , Prognosis , Proportional Hazards Models , Retrospective Studies , Risk Factors , Serum Albumin/analysis , Sodium/blood , Survival Analysis , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/diagnosis , Tertiary Care Centers
14.
Cancer Res Treat ; 47(4): 591-9, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25672585

ABSTRACT

PURPOSE: In response to the challenges and difficulties imposed by rare cancers, multi-stakeholder initiatives dedicated to improving rare cancer care was launched, and several recommendations were made by professional societies. However, these primarily reflect the view of the advocates and supporters, and may not represent the views of the "average" clinician or researcher. In this study, we sought to investigate perceived difficulties with regard to rare cancer care and potential solutions endorsed by oncologists. MATERIALS AND METHODS: A representative sample of 420 oncologists recruited in 13 cancer centers participated in a nationwide survey. RESULTS: Oncologists faced various difficulties in treatment of patients with rare cancers, including the lack of clinical practice guidelines (65.7%) and personal experience (65.2%), lack of approved treatment options (39.8%), and reimbursement issues (44.5%). They were generally supportive of recent recommendations by multi-stakeholder initiatives as well as professional societies for development of clear clinical practice guidelines (66.0%), flexible reimbursement guidelines (52.9%), and a national rare cancer registry (47.4%). However, there was only moderate endorsement for referrals to high-volume centers (35.5%) and encouragement of off-label treatments (21.0%). CONCLUSION: Insights into the general attitudes of oncologists gained through our nationwide survey of representative samples would be helpful in development of clinical practices and public health policies in rare cancer treatment and research.


Subject(s)
Delivery of Health Care , Neoplasms , Oncologists/psychology , Surveys and Questionnaires , Adult , Female , Humans , Male , Republic of Korea
15.
Liver Int ; 35(10): 2246-55, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25682719

ABSTRACT

BACKGROUND/AIMS: Transient elastography (TE) has become an alternative to liver biopsy (LB). This study investigated the diagnostic performance of liver stiffness (LS) measurement using TE in Korean patients with chronic hepatitis B and C (CHB and CHC). METHODS: From April 2006 to June 2014, 916 patients (567 CHB and 349 CHC) who underwent LB and TE at 15 centres were analyzed. The Batts and Ludwig scoring system was used for histologic assessment. Aspartate aminotransferase (AST)-to-platelet ratio indexes (APRI) were calculated. Area under the receiver operating characteristic curve (AUROC) was used. RESULTS: The median age, LS value, and APRI score were 45 years, 8.8 kPa, and 0.61, respectively, in CHB patients vs. 51 years, 6.8 kPa and 0.55, respectively, in CHC patients. TE was significantly superior to APRI in CHB patients (AUROC 0.774 vs. 0.72 for ≥F2, 0.849 vs. 0.812 for ≥F3, and 0.902 vs. 0.707 for F4, respectively; all P < 0.05). Furthermore, TE was significantly superior for predicting ≥ F3 stage (AUROC 0.865 vs. 0.840, P = 0.009) whereas it was similar for predicting ≥ F2 and F4 stage (AUROC 0.822 vs. 0.796; 0.910 vs. 0.884; all P > 0.05) in CHC patients. In CHB patients, optimal cut-off LS values were 7.8 kPa for ≥F2, 8.2 kPa for ≥ F3, and 11.6 kPa for F4, vs. 6.8 kPa, 8.6 kPa, and 14.5 kPa, respectively, in CHC patients. CONCLUSIONS: TE can accurately assess the degree of liver fibrosis in Korean patients with CVH. TE was superior to APRI for predicting each fibrosis stage.


Subject(s)
Biomarkers/analysis , Elasticity Imaging Techniques/methods , Hepatitis B, Chronic/complications , Hepatitis C, Chronic/complications , Liver Cirrhosis/diagnosis , Liver/pathology , Adult , Area Under Curve , Biopsy , Female , Humans , Liver Cirrhosis/pathology , Male , Middle Aged , Multivariate Analysis , ROC Curve , Republic of Korea , Retrospective Studies
16.
J Hepatol ; 62(6): 1278-86, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25617504

ABSTRACT

BACKGROUND & AIMS: Altered expression of dual specificity phosphatase 1 (DUSP1) is common in tumors including hepatocellular carcinoma (HCC), and is predictive of tumor progression and poor prognosis. However, the tumor suppressive role of DUSP1 has yet to be clearly elucidated. METHODS: The molecular mechanisms of tumor suppression that were investigated were induction of apoptosis, cell cycle inhibition, and regulation of p53. Additionally, the antitumor effect of DUSP1 was assessed using a mouse model. Associated signaling pathways in HCC cells and tissues were examined. RESULTS: Downregulation of DUSP1 expression was significantly correlated with poor differentiation (p<0.001) and advanced HCC stage (p=0.023). DUSP1 expression resulted in HCC suppression and longer survival (p=0.0002) in a xenoplant mice model. DUSP1 inhibited p38 MAPK phosphorylation and subsequently suppressed HSP27 activation, resulting in enhanced p53 phosphorylation at sites S15, S20, and S46 in HCC cells. Enhanced p53 activation induced the expression of target genes p21 and p27, which are linked to cell cycle arrest and apoptosis. Thus, DUSP1 was potentially linked to p53 activation via the p38 MAPK/HSP27 pathway. Wild-type but not mutant p53 transcriptionally upregulated DUSP1 via its DNA-binding domain. DUSP1 and p53 might collaborate to suppress tumors in hepatocarcinogenesis via a positive regulatory loop. CONCLUSIONS: Our results revealed that disruption of a positive regulatory loop between DUSP1 and p53 promoted HCC development and progression, providing a rationale for a therapeutic agent that restores DUSP1 in HCC.


Subject(s)
Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/metabolism , Dual Specificity Phosphatase 1/metabolism , Liver Neoplasms/etiology , Liver Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Animals , Apoptosis , Carcinoma, Hepatocellular/pathology , Cell Cycle Checkpoints , Cell Differentiation , Cell Line, Tumor , Disease Progression , Down-Regulation , Dual Specificity Phosphatase 1/genetics , HCT116 Cells , Hep G2 Cells , Heterografts , Humans , Liver Neoplasms/pathology , Mice , Mice, Nude , Mutation , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Signal Transduction , Tumor Stem Cell Assay , Tumor Suppressor Protein p53/genetics
17.
Gut Liver ; 9(3): 395-404, 2015 May 23.
Article in English | MEDLINE | ID: mdl-25473072

ABSTRACT

BACKGROUND/AIMS: We investigated factors associated with the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients during long-term oral nucleos(t)ide analog (NA) therapy. METHODS: This retrospective study included 524 naive CHB patients who received oral NA therapy for more than 48 weeks between January 2003 and December 2007. The primary outcome was 5-year cumulative probability of disease progression and HCC development. Disease progression was defined as cirrhosis development, cirrhotic complications, HCC or liver-related mortality. RESULTS: For the 524 patients, the cumulative probabilities of disease progression and HCC development at 1, 2, 3, 4 and 5 years were 1.1%, 6.3%, 9.0%, 11.6%, and 16.2% and 0.2%, 1.8%, 3.6%, 5.8%, and 9.3%, respectively. In multivariate analysis, age >50 years (hazard ratio [HR], 1.05) and cirrhosis (HR, 2.95) were significant factors for disease progression. Similarly, age >50 years (HR, 1.05), family history of HCC (HR, 5.48), and cirrhosis (HR, 17.16) were significant factors for HCC development. Importantly, longer duration (>12 months) of maintained virological response (<20 IU/mL) reduced the risks of disease progression (HR, 0.19) and HCC development (HR, 0.09). CONCLUSIONS: Longer duration of maintained virological response significantly reduces the risk of disease progression or HCC development in CHB patients undergoing long-term oral NA therapy.


Subject(s)
Antiviral Agents/administration & dosage , Disease Progression , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/pathology , Adult , Age Factors , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/etiology , Female , Hepatitis B, Chronic/complications , Humans , Liver Cirrhosis/epidemiology , Liver Cirrhosis/etiology , Liver Neoplasms/epidemiology , Liver Neoplasms/etiology , Male , Middle Aged , Proportional Hazards Models , Retrospective Studies , Time
18.
Int J Oncol ; 46(3): 1121-30, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25502339

ABSTRACT

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human TRAIL has been evaluated in clinical trials, however, various malignant tumors are resistant to TRAIL. Parthenolide (PT) has recently been demonstrated as a highly effective anticancer agent and has been suggested to be used for combination therapy with other anticancer agents. In this study, we investigate the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. HT-29 (TRAIL-resistant) and HCT116 (TRAIL-sensitive) cells were treated with PT and/or TRAIL. The results demonstrated that combined treatment induced apoptosis which was determined using MTT, cell cycle analysis, Annexin V assay and Hoechst 33258 staining. Interestingly, we confirmed that HCT116 cells have much higher death receptor (DR) 5 than HT-29 cells and PT upregulates DR5 protein level and surface expression in both cell lines. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, p53 cytochrome C release, and caspase cascades. These results suggest that PT sensitizes TRAIL-induced apoptosis via upregulation of DR5 and mitochondria-dependent pathway. Combination treatment using PT and TRAIL may offer an effective strategy to overcome TRAIL resistance of certain CRC cells.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Colorectal Neoplasms/drug therapy , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Sesquiterpenes/pharmacology , TNF-Related Apoptosis-Inducing Ligand/therapeutic use , Cell Death/drug effects , Cells, Cultured , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Drug Synergism , HCT116 Cells , HT29 Cells , Humans , Up-Regulation/drug effects
19.
Bioorg Med Chem Lett ; 24(17): 4080-3, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25124116

ABSTRACT

Erythropoietin-producing hepatocellular receptor tyrosine kinase subtype A2 (EphA2) is an attractive therapeutic target for suppressing tumor progression. In our efforts to discover novel small molecules to inhibit EphA2, a class of compound based on 4-substituted quinazoline containing 7-(morpholin-2-ylmethoxy) group was identified as a novel hit by high throughput screening campaign. Structural modification of parent quinazoline scaffolds by introducing substituents on aniline displayed potent inhibitory activities toward EphA2.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Receptor, EphA2/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Receptor, EphA2/metabolism , Structure-Activity Relationship
20.
Gastrointest Endosc ; 80(3): 447-55, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24679659

ABSTRACT

BACKGROUND: Objective evaluation tools for assessing the effectiveness of stenting in palliative treatment of malignant biliary obstruction are not satisfactory. Effects of biliary stenting on liver volume change have never been studied. OBJECTIVE: We aimed to use volumetry to analyze liver volume changes after endoscopic stenting in bile duct cancer according to the location and number of stents. DESIGN: Retrospective review. SETTING: University hospital. PATIENTS: Patients with a diagnosis of hilar or distal bile duct cancer and who underwent biliary metal stenting. INTERVENTIONS: ERCP with self-expandable metal stent placement. MAIN OUTCOME MEASUREMENTS: Liver volume change after biliary stenting and its comparison according to the location (hilar vs distal common bile duct) and number (hilar bilateral vs hilar unilateral). RESULTS: There were 60 patients; 31 were treated for hilar bile duct cancer (13 for bilateral stent and 18 for unilateral stent) and 29 for distal bile duct cancer. Overall mean follow-up duration was 11.7 ± 4.9 weeks. Liver volume increased 17.4 ± 24.1%. The rate of liver growth was rapid during the early period from 4 to 8 weeks. Stenting in hilar bile duct cancer tended to increase liver volume more than distal biliary stents (22.5% vs 11.9%, P = .091). In hilar bile duct cancer, unilateral and bilateral stents showed similar liver volume increases (20.1% and 25.8%, respectively; P = .512). LIMITATIONS: Single center, retrospective. CONCLUSIONS: Biliary stenting markedly increased liver volume in both hilar and distal bile duct cancer. Our data suggest that liver volume assessment could be a useful tool for evaluating stent efficacy.


Subject(s)
Bile Duct Neoplasms/surgery , Bile Ducts, Intrahepatic/surgery , Cholangiocarcinoma/surgery , Cholestasis/surgery , Liver/pathology , Stents , Aged , Aged, 80 and over , Bile Duct Neoplasms/complications , Bile Duct Neoplasms/pathology , Cholangiocarcinoma/complications , Cholangiocarcinoma/pathology , Cholangiopancreatography, Endoscopic Retrograde , Cholestasis/etiology , Female , Humans , Liver/diagnostic imaging , Male , Middle Aged , Organ Size , Palliative Care , Retrospective Studies , Treatment Outcome
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