• BMB Reports
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• v.45 no.6
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• pp.365-370
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• 2012

Hepatitis B virus (HBV) DNA is often integrated into hepatocellular carcinoma (HCC). Although the relationship between HBV integration and HCC development has been widely studied, the role of HBV integration in HCC development is still not completely understood. In the present study, we constructed a pooled BAC library of 9 established cell lines derived from HCC patients with HBV infections. By amplifying viral genes and superpooling of BAC clones, we identified 2 clones harboring integrated HBV DNA. Screening of host-virus junctions by repeated sequencing revealed an HBV DNA integration site on chromosome 11q13 in the SNU-886 cell line. The structure and rearrangement of integrated HBV DNA were extensively analyzed. An inverted duplicated structure, with fusion of at least 2 HBV DNA molecules in opposite orientations, was identified in the region. The gene expression of cancer-related genes increased near the viral integration site in HCC cell line SNU-886.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.2019-2025
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• 2016

Hepatocellular carcinoma (HCC) is major health problem with high mortality rates, especially in patients with hepatitis B virus (HBV) infection. Telomerase function is one of common mechanisms affecting genome stability and cancer development. Recent studies demonstrated that genetic polymorphisms of telomerase associated genes such as telomerase associated protein 1 (TEP1) rs1713449 and PIN2/TERF1-interacting telomerase inhibitor 1 (PINX1) rs1469557 may be associated with risk of HCC and other cancers. In this study, 325 patients with HCC and 539 non-HCC groups [193 healthy controls, 80 patients with HBV-related liver cirrhosis (LC) and 266 patients with HBV-related chronic hepatitis (CH)] were enrolled to explore genetic polymorphisms of both SNPs using the allelic discrimination method based on MGB probe TaqMan real time PCR. We demonstrated that all genotypes of both genes were in Hardy-Wienberg equilibrium (P>0.05). Moreover, there was no significant association between rs1713449 genotypes and HCC risk, HCC progression and overall survival (P>0.05). Interestingly, we observed positive association of rs1469557 with risk of HCC when compared with the LC group under dominant (CC versus CT+TT, OR=1.89, 95% CI= 1.06-3.40, P=0.031) and allelic (C versus T alleles, OR=1.75, 95% CI=1.04-2.94, P=0.033) models, respectively. Moreover, overall survival of HCC patients with CC genotype of rs1469557 was significantly higher than non-CC genotype (Log-rank P=0.015). These findings suggest that PINX1 rs1469557 but not TEP1 rs1469557 might play a role in HCC progression in Thai patients with LC and be used as the prognosis marker to predict overall survival in HCC patients.

• BMB Reports
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• v.45 no.11
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• pp.629-634
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• 2012

The human glycoprotein, stanniocalcin 2 (STC2) plays multiple roles in several tumor types, however, its function and clinical significance in hepatocellular carcinoma (HCC) remain unclear. In this study, we detected STC2 expression by quantitative real-time PCR and found STC2 was upregulated in HCC tissues, correlated with tumor size and multiplicity of HCC. Ectopic expression of STC2 markedly promoted HCC cell proliferation and colony formation, while silencing of endogenous STC2 resulted in a reduced cell growth by cell cycle delay in G0/G1 phase. Western blot analysis demonstrated that STC2 could regulate the expression of cyclin D1 and activate extracellular signal-regulated kinase 1/2 (ERK1/2) in a dominant-positive manner. Transwell chamber assay also indicated altered patterns of STC2 expression had an important effect on cell migration. Our findings suggest that STC2 functions as a potential oncoprotein in the development and progression of HCC as well as a promising molecular target for HCC therapy.

• Journal of Digestive Cancer Reports
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• v.8 no.1
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• pp.65-70
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• 2020

Although being one of the major causes of malignancy related death globally, hepatocellular carcinoma (HCC) has not received much attention in respect of novel drug development. Fortunately, several new drugs were found to be effective and tolerable in patients with advanced HCC from a number of phase 3 studies during the recent several years. Novel multi-targeted kinase inhibitors and immune checkpoint inhibitors were approved for clinical use, and combination strategies to maximize the potent of drugs demonstrated promising antitumor activity and safety with high response rate and improved safety profile. The increased number of available agents for HCC will contribute to change of treatment strategies and prognosis of patients with advanced HCC. Still, there is a many critical questions remain unanswered. Currently ongoing trials and future studies will provide better understanding of tumor biology and optimized criteria for patient selection and combination therapies.

• Journal of Korea Technical Association of The Pulp and Paper Industry
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• v.47 no.4
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• pp.76-80
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• 2015

In filler loaded paper, the size of the filler affects its strength, optical and surface properties. As the size of the filler increases, tensile strength and bulk usually increases, opacity decreases, and smoothness becomes worse. Pre-flocculation of GCC (grounded calcium carbonate) makes large diameter flocs at aqueous medium that consists of multiple GCC particles, but they collapse to 2-dimensional shape in dried paper and makes low bulk paper. The hybrid calcium carbonate (HCC) that was made by in-situ $CaCO_3$ formation between GCC in aqueous medium made high bulk paper without harming tensile strength, bulk, opacity, and smoothness. The GCC that has equivalent size as HCC failed to make high opacity and smoothness as much as HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.8
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• pp.4509-4513
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• 2013

Chronic hepatitis B virus (HBV) infection has long been the most common cause of hepatocellular carcinoma (HCC). However, some aspects of the pathogenesis of HBV infection and genesis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) are still inconclusive. An increasing number of published studies indicate that hepatitis B virus mutations are associated with risk of HCC. These variations include, in particular, mutations in ORF S,C,X gene regions. This mini-review summarizes results of clinical studies and molecular mechanisms on the possible relations of HBV mutations with the development of hepatocellular carcinoma.

• The Korean Journal of Physiology and Pharmacology
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• v.17 no.5
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• pp.375-383
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• 2013

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is thought to account for more than 80% of primary liver cancers. Both HBV and HCV can establish chronic liver inflammatory infections, altering hepatocyte and liver physiology with potential liver disease progression and HCC development. Cyclophilin A (CypA) has been identified as an essential host factor for the HCV replication by physically interacting with the HCV non structural protein NS5A that in turn interacts with RNA-dependent RNA polymerase NS5B. CypA, a cytosolic binding protein of the immunosuppressive drug cyclosporine A, is overexpressed in many cancer types and often associated with malignant transformation. Therefore, CypA can be a good target for molecular cancer therapy. Because of antiviral activity, the CypA inhibitors have been tested for the treatment of chronic hepatitis C. Nonimmunosuppressive Cyp inhibitors such as NIM811, SCY-635, and Alisporivir have attracted more interests for appropriating CypA for antiviral chemotherapeutic target on HCV infection. This review describes CypA inhibitors as a potential HCC treatment tool that is contrived by their obstructing chronic HCV infection and summarizes roles of CypA in cancer development.

• Proceedings of the KSAR Conference
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• 2003.06a
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• pp.54-54
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• 2003

The activation of protooncogenes or the inactivation of their gene products may be a specific and effective functional study for human neoplasia. To examine this possibility, we have used the tetracycline regulatory system to generate transgenic mice that conditionally express the HccR-2 protooncogene in vivo. The new human cervical cancer protooncogene (HccR-2) was detected from cervical cancer cell line. To elucidate its biological functions, we generated transgenic mice that expressed the HccR-2 gene. The sustained expression of the HccR-2 transgene culminated chronic neutrophilic leukemia (CNL). CNL is a rare chronic myeloproliferative disorder that presents as a sustained, mature neutrophilic leukocytosis with few or no circulating immature granulocytes, the absence of peripheral blood monocytosis, basophilia, or eosinophilia, and infiltration of neutrophils at the liver, spleen and kidney. Mice expressing the HccR-2 and tetracycline-transactivating protein (tTa) transgene were found to have altered myeloid development that was characterized by increased percentages of mature neutrophil and band form neutrophil in the peripheral blood, liver and spleen. Activation of the transgene causes CNL. In our model, expression of HccR-2 transgene mice was similar in many respects to the human CNL. This model will be valuable not only for investigating the biological properties of the HccR-2 and other protooncogenes in vivo but also for analyzing the mechanism involved in the progression of CNL.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.12
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• pp.4969-4976
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• 2014

Background: miR-152 is involved in the genesis and development of several malignancies. However, its role in HCC has not been fully clarified. The aim of this study was to investigate the clinicopathological significance of miR-152 and its effect on the malignant phenotype of HCC cells. Methods: miR-152 expression was detected using real-time quantitative RT-PCR in 89 pairs of HCC formalin-fixed paraffin-embedded and their adjacent tissues. Functionally, in vitro effects and mechanisms of action of miR-152 on proliferation, viability, caspase activity, apoptosis and motility were explored in HepG2, HepB3 and SNU449 cells, as assessed by spectrophotometry, fluorimetry, fluorescence microscopy, wound-healing and Western blotting, respectively. Results: miR-152 expression in HCC was downregulated remarkably compared to that in adjacent hepatic tissues. miR-152 levels in groups of advanced clinical stage, larger tumor size and positive HBV infection, were significantly lower than in other groups. A miR-152 mimic could suppress cell growth, inhibit cell motility and increase caspase activity and apoptosis in HCC cell lines. Furthermore, Western blotting showed that the miR-152 mimic downregulated Wnt-1, DNMT1, ERK1/2, AKT and TNFRS6B signaling. Intriguingly, inverse correlation of TNFRF6B and miR-152 expression was found in HCC and bioinformatics confirmed that TNFRF6B might be a target of miR-152. Conclusions: Underexpression of miR-152 plays a vital role in hepatocarcinogenesis and lack of miR-152 is related to the progression of HCC through deregulation of cell proliferation, motility and apoptosis. miR-152 may act as a tumor suppressor miRNA by also targeting TNFRSF6B and is therefore a potential candidate biomarker for HCC diagnosis, prognosis and molecular therapy.

• Genomics & Informatics
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• v.8 no.1
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• pp.9-18
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• 2010

Integrins are transmembrane receptor proteins that mediate cell-cell adhesion and cell-extracellular matrix (ECM) adhesion. The deregulation of cell-ECM adhesion and the abnormal expression of beta1 (${\beta}1$) integrins (ITGB1s) are involved in tumor development and metastasis. In the liver, the expression of integrins and ECM proteins can be a cause of hepatocellular carcinoma (HCC) development. We performed direct DNA sequencing of 24 individuals, and identified 23 sequence variants of ITGB1 polymorphisms. Among these 23 variants, 7 common variants were selected based on frequencies and linkage disequilibrium, and then genotyped in a larger-scale group of subjects (n=1,103). The genetic associations of ITGB1 polymorphisms with the clearance of HBV and HCC outcome of HBV patients were analyzed using logistic regression models and Cox relative hazard models. Although there was no significant association observed between the polymorphisms and the HCC outcome of HBV patients, the second most common haplotype (ITGB1 haplotype-2 [C-C-C-C-T-C-T]) was putatively associated with HBV clearance (OR=0.75, p=0.008 and $P^{corr}=0.05$). The minor allele frequency (MAF) of ITGB1 haplotype -2 of the spontaneously recovered (SR) group was significantly higher than that of the chronic carrier group (CC) (freq. = 0.248 vs. 0.199). The information derived from this study could be valuable for understanding the genetic factors involved in the clearance of HBV.