Model to Predict Recurrence after Living Donor Liver Transplantation for Hepatocellular Carcinoma beyond the Milan Criteria

Yuri Cho,Jeong-Hoon Lee,Dong Hyeon Lee,Hyeki Cho,Hongkeun Ahn,Minjong Lee,Jeong-ju Yoo,Won-mook Choi,Young Youn Cho,Yun Bin Lee,Su Jong Yu,Nam-Joon Yi,Kwang-Woong Lee,Seoung Hoon Kim,Jong Man Kim,Jae- 한국간담췌외과학회 2014 한국간담췌외과학회 학술대회지 Vol.2014 No.4

HCV, Acute, LT : Model to Predict Recurrence after Living Donor Liver Transplantation for Hepatocellular Carcinoma beyond the Milan Criteria

( Yuri Cho ),( Jeong Hoon Lee ),( Dong Hyeon Lee ),( Min Jong Lee ),( Jeong Ju Yoo ),( Won Mook Choi ),( Young Youn Cho ),( Yun Bin Lee ),( Eun Ju Cho ),( Su Jong Yu ),( Nam Joon Yi ),( Kwang Woong Le 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background/aims: Some patients with hepatocellular carcinoma (HCC) beyond the Milan criteria (MC) have favorable tumor biology, and that these patients would have low risk of tumor recurrence after living donor liver transplantation (LDLT). This study was designed to develop a model of tumor recurrence after LDLT for HCC beyond the MC, so as to select the best candidates for LDLT in HCC beyond the MC. Methods: Consecutive patients who had undergone LDLT beyond the MC at Seoul National University Hospital between September 2001 and January 2013 were analyzed. Demographic, clinical, and tumor characteristics were evaluated and a model to predict recurrence after LDLT (MoRAL score) was created. Results: A total of 104 patients were included. The median follow-up was 52.7 (range, 1.6-157.5) months. Their 5-year overall survival and cumulative recurrence rates were 70.4% and 41.8%, respectively. In multivariate analysis, independent pretransplant risk factors for HCC recurrence were serum AFP (OR=1.003, P=0.013) and PIVKA-II (OR=1.001, P=0.050) levels. AFP reflected maximal tumor size and PIVKA-II reflected tumor number and type (nodular or diffuse/infiltrative) (all P<0.001). Using Cox proportional hazards model, MoRAL score ( )was derived (median, 108.3; range 33.7-3928.3). The concordance statistic of MoRAL (0.836) was superior to CLIP score (0.772), TNM stage (0.600), JIS stage (0.601) and T classification (0.626). The tumor recurrence after LDLT was significantly related to mortality (OR=21.6, P<0.001). Conclusions: A new model to predict tumor recurrence of HCC patients beyond the MC after LDLT based on objective parameters provides refined prognostication (Figure 1). External validation is warranted.

Modified AS1411 Aptamer Suppresses Hepatocellular Carcinoma by Up-regulating Galectin-14

( Hyeki Cho ),( Yun Bin Lee ),( Yuri Cho ),( Jeong-hoon Lee ),( Dong Hyeon Lee ),( Jeong-ju Yoo ),( Young Youn Cho ),( Eun Ju Cho ),( Su Jong Yu ),( Yoon Jun Kim ),( Jong In Kim ),( Jong Hun Im ),( Ju 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Aptamers are small synthetic oligonucleotides that bind to target proteins with high specificity and affinity. AS1411 is an aptamer that binds to the protein nucleolin, which is overexpressed in the cytoplasm and occurs on the surface of cancer cells. We investigated the therapeutic potential of aptamers in treating hepatocellular carcinoma (HCC) by evaluating anti-tumor effects and confirming the affinity and specificity of AS1411 and modified AS1411 aptamers in HCC cells. Methods: Cell growth was assessed using the MTS assay, and cell death signaling was explored by immunoblot analysis. Fluore- scence-activated cell sorting was performed to evaluate the affinity and specificity of AS1411 aptamers in SNU-761 HCC cells. We investigated the in vivo effects of the AS1411 aptamer using BALB/c nude mice in a subcutaneous xenograft model with SNU-761 cells. Results: Treatment with a modified AS1411 aptamer significantly decreased in vitro (under normoxic [P=0.035] and hypoxic [P=0.018] conditions) and in vivo (under normoxic conditions, P=0.041) HCC cell proliferation compared to control aptamers. AS1411 and control aptamers failed to control HCC cell proliferation. However, AS1411 and the modified AS1411 aptamer did not induce caspase activation. Decrease in cell growth by AS1411 or modified AS1411 was not prevented by caspase or necrosis inhibitors. In a microarray, AS1411 significantly enhanced galectin-14 expression. Suppression of HCC cell proliferation by the modified AS1411 aptamer was attenuated by galectin-14 siRNA transfection. Conclusions: The modified AS1411 aptamer suppressed HCC cell growth in vitro and in vivo by up-regulating galectin-14 expression. Modified AS1411 aptamers may have therapeutic potential as a novel targeted therapy for HCC.

Original Article : Sofosbuvir-based therapy for patients with chronic hepatitis C: Early experience of its efficacy and safety in Korea

( Yuri Cho ),( Eun Ju Cho ),( Jeong Hoon Lee ),( Su Jong Yu ),( Jung Hwan Yoon ),( Yoon Jun Kim ) 대한간학회 2015 Clinical and Molecular Hepatology(대한간학회지) Vol.21 No.4

Background/Aims: The previous standard treatment for chronic hepatitis C (CHC) patients, comprising a combination of pegylated interferon (IFN) and ribavirin, was associated with suboptimal efficacy and severe adverse reactions. A new era of direct-acting antivirals is now dawning in Korea. Early experience of applying sofosbuvir-based therapy to CHC patients in Korea is reported herein. Methods: Data on efficacy and safety were collected for CHC patients treated with a combination of sofosbuvir plus ribavirin or sofosbuvir/ledipasvir with or without ribavirin. Results: This retrospective study included 25 consecutive patients who received sofosbuvir-based therapy (19 with genotype 1b and 6 with genotype 2) at Seoul National University Hospital from May 2014 to April 2015. A virologic response was achieved at week 4 by 85.7% and 80% of the patients with genotypes 1b and 2, respectively. The HCV-RNA level decreased more slowly in IFN-experienced than in treatment-naive patients with genotype 1b. However, the sustained virologic response at week 12 (SVR12) rate did not differ among these patients, and was as high as 100%. The presence of cirrhosis significantly increased the risk of a virologic response failure at week 4 (OR, 11.0; P=0.011) among patients with HCV genotype 1b. Only five patients (20%) experienced minor adverse events, including grade 1 fatigue and headache. The hemoglobin level decreased slightly after sofosbuvir-based therapy, but there was no case of premature discontinuation of this therapy. Conclusions: In a real clinical practice, sofosbuvir-based therapy for CHC patients in Korea achieved optimal antiviral efficacy with insignificant adverse events. Long-term follow-up data are warranted to ensure the sustained antiviral efficacy and long-term safety of sofosbuvir-based IFN-free therapy. (Clin Mol Hepatol 2015;21:358-364)

ROS Induced-Activation of YAP-1 through a C-Myc Pathway Is a Therapeutic Target in Hepatocellular Carcinoma

( Yuri Cho ),( Min Ji Park ),( Koeun Kim ),( Jung-hwan Yoon ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The Hippo signaling pathway regulates organ size by controlling both cell proliferation and apoptosis via effectors such as yes-associated protein (YAP). Dysregulation of the Hippo pathway has been suggested as one of the therapeutic target in hepatocarcinogenesis. Reactive oxygen species (ROS) levels increase during the progression from early to advanced hepatocellular carcinoma (HCC). Activated YAP-1 by ROS-induced damage has been hypothesized to aggravate progression of HCC, but it remains unclear which signaling pathway is involved. Here, we investigated ROS-induced YAP-1 activation in HCC and the signaling pathway which is associated. Methods: The expression of YAP-1 was quantified using real-time PCR and immunoblotting. Human HCC cells (Huh-7, HepG2, and SNU-761) were grown under H₂O₂ treatment which is a major component of ROS in living organisms, either with YAP-1 siRNA or with control siRNA. MTT assays were performed to evaluate the role of YAP-1 in HCC under H₂O₂ treatment. To investigate the signaling pathway responsible for the activation of YAP-1, immunoblotting was performed. Results: H₂O₂ treatment increased the mRNA and protein expressions of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761). Suppression of YAP-1 using siRNA transfection resulted in significant decrease in tumor proliferation under H₂O₂ treatment both in vitro and in vivo. The oncogenic action of YAP-1 occurred via activation of the c-myc pathway, leading to up-regulation of unfolded protein response (UPR), including the 78-kDa glucose-regulated protein (GRP78/BiP) and activating transcription factor 6 (ATF-6). Conclusions: These results indicate that ROS-induced activation of YAP-1 via the c-myc pathway, which leads to activation of the UPR pathway, is a therapeutic target in HCC.

Preventive strategy for nonalcoholic fatty liver disease-related hepatocellular carcinoma

Yuri Cho,Bo Hyun Kim,Joong-Won Park 대한간학회 2023 Clinical and Molecular Hepatology(대한간학회지) Vol.29 No.-

The incidence of hepatocellular carcinoma (HCC) associated with nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide, including Asia. Most patients with NAFLD-related HCC are at a much-advanced stage and older age at the time of diagnosis than those with virus-related HCC because they have not undergone HCC surveillance. This review provides an overview of the mechanism of hepatocarcinogenesis in NAFLD, preventive strategies for NAFLD-related HCC, and strategies for the surveillance of patients with NAFLD.

Overview of Asian clinical practice guidelines for the management of hepatocellular carcinoma: An Asian perspective comparison

Yuri Cho,Bo Hyun Kim,Joong-Won Park 대한간학회 2023 Clinical and Molecular Hepatology(대한간학회지) Vol.29 No.2

Hepatocellular carcinoma (HCC) is highly prevalent and the third most common cause of cancer-related death in Asia. In contrast to the West, the main etiology of HCC in many Asian countries except Japan is chronic hepatitis B virus infection. Differences in the major causes of HCC lead to significant clinical and treatment differences. This review summarizes and compares guidelines on managing HCC from China, Hong Kong, Taiwan, Japan, and South Korea. From oncology and socio-economic perspectives, factors such as underlying diseases, staging methods, government policies, insurance coverage, and medical resources contribute to varying treatment strategies among countries. Furthermore, the differences in each guideline are fundamentally caused by the lack of incontrovertible medical evidence, and even existing results of clinical trials can be interpreted differently. This review will provide a complete overview of the current Asian guidelines for HCC in recommendations and in practice.

Age-Related Effects of Sodium Arsenite on Splenocyte Proliferation and Th1/Th2 Cytokine Production

Yuri Cho,김대경,Kyong Hoon Ahn,백문정,최종민,Jung Eun Ji,Jong Hoon Won,Zhicheng Fu,Ji Min Jang 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.2

Aging is associated with immune dysfunction and conditions such as inflamm-aging and immunosuppression. Arsenic, an environmental contaminant distributed worldwide, affects the immune system. This study tested the hypothesis that arsenic has distinct effects on T cell proliferation and the production of cytokines by activated T cells. Murine splenocytes from young (2 months) and aged (24-26 months) C57BL/6 mice were exposed to arsenite (As3+), the most toxic form of inorganic arsenic, and stimulated with concanavalin A (Con A) or anti-CD3 antibody. T cell proliferation decreased significantly in response to Con A and anti-CD3 at subtoxic doses of arsenite in splenocytes from both young and aged mice. Arsenite, added concurrently with Con A or anti-CD3, significantly inhibited the production of interleukin-2 (IL-2), interferon-γ (IFN-γ), and interleukin-4 (IL-4) by splenocytes from young mice and significantly reduced the production of IL-10 by splenocytes from aged mice. In contrast, the production of IL-2 and IL-4 by splenocytes from aged mice was only slightly affected by arsenite. The results show that arsenic exposure reduces the immune response in splenocytes. Moreover,this effect may be influenced by aging.

Doxycycline is Neuroprotective Against Nigral Dopaminergic Degeneration by a Dual Mechanism Involving MMP-3

Cho, Yuri,Son, Hyo Jin,Kim, Eun-Mee,Choi, Ji Hyun,Kim, Sung Tae,Ji, In Jung,Choi, Dong Hee,Joh, Tong H.,Kim, Yoon Seong,Hwang, Onyou Springer-Verlag 2009 Neurotoxicity research Vol.16 No.4

Tumor-Stroma Crosstalk Enhances REG3A Expressions that Drives the Progression of Hepatocellular Carcinoma

( Yuri Cho ),( Min Ji Park ),( Koeun Kim ),( Jung-hwan Yoon ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Crosstalk between tumor cells and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). In this study, we investigated the key signal that modulates crosstalk between HCC cells and their microenvironment. Methods: Human HCC cell lines (Huh-7, HepG2, and SNU- 761) were cocultured with an activated human hepatic stellate cell line (HSCs; LX-2) under normoxic (20% O2 and 5% CO2, at 37 ºC) conditions. Complementary DNA (cDNA) microarray analysis was performed to find the molecule which is significantly enhanced by crosstalk between HCC cells and stroma. In vivo study using a subcutaneous xenograft model by injecting MH134 cells (C3H mice) was performed to confirm the effect of coculturing HCC cells and HSC cells and the inhibitory effect by small interfering RNA (siRNA) transfection. Immunoblot analyses were used to investigate the signaling pathway. Results: Using cDNA microarray analysis, we found the molecule, REG3A, which was significantly enhanced by coculturing Huh-7 cells and HSC cells (+ 8.2 log) as compared to mono-culturing Huh-7 cells. Coculturing HCC cells (Huh-7, HepG2, and SNU-761) with HSC cells enhanced the mRNA and protein expressions of REG3A as compared to mono-culturing HCC cells. Downregulation of REG3A by siRNA significantly decreased the proliferation of tumor cells in vitro and in vivo, when HCC cells were cocultured with HSCs (both P<0.05). In immunoblot assay, downregulation of REG3A by siRNA decreased the expressions of phosphorylated p42/44 and β-catenin, especially when HCC cells were cocultured with HSCs. Immunofluorescence study also revealed that deoxycholic acid-induced HCC cell apoptosis was inhibited when REG3A was down-regulated in HSCs-cocultured HCC cells. Interestingly, crosstalk-induced REG3A up-regulation was modulated by PDGF-β in p42/44-dependent manner. Conclusions: In conclusion, crosstalk between HCC cells and HSCs cells was modulated by up-regulation of REG3A in p42/44-dependent manner. Moreover, the up-regulation of REG3A by crosstalk between HCCs and HSCs was mediated by PDGF-β. Targeting REG3A might be a novel therapeutic target in the management of human HCCs by inhibiting crosstalk between HCCs and HSCs.