• The Korean Journal of Physiology and Pharmacology
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• v.20 no.3
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• pp.237-243
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• 2016

Oleanolic acid (OA) has a wide variety of bioactivities such as hepatoprotective, anti-inflammatory and anti-cancer activity and is used for medicinal purposes in many Asian countries. In the present study, the effect of OA on induction of autophagy in human hepatocellular carcinoma HepG2 and SMC7721 cells and the related mechanisms were investigated. MTT assay showed that OA significantly inhibited HepG2 and SMC7721 cells growth. OA treatment enhanced formation of autophagic vacuoles as revealed by monodansylcadaverine (MDC) staining. At the same time, increasing punctuate distribution of microtubule-associated protein 1 light chain 3 (LC3) and an increasing ratio of LC3-II to LC3-I were also triggered by OA incubation. In addition, OA-induced cell death was significantly inhibited by autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) pretreatment. And we found out that OA can suppress the PI3K/Akt1/mTOR signaling pathway. Furthermore, our data suggested that OA-triggered autophagy was ROS-dependent as demonstrated by elevated cellular ROS levels by OA treatment. When ROS was cleared by N-acetylcysteine (NAC), OA-induced LC3-II convertsion and cell death were all reversed. Taken together, our results suggest that OA exerts anticancer effect via autophagic cell death in hepatocellular carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10085-10089
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• 2015

Background: The insulin-like growth factor (IGF) system comprises a group of proteins that play key roles in regulating cell growth, differentiation, and apoptosis in a variety of cellular systems. The aim of this study was to investigate the role of insulin-like growth factor binding protein 3 (IGFBP3) in hepatocellular carcinoma. Materials and Methods: Expression of IGF2, IGFBP3, and PTEN was analyzed by qRT-PCR. Lentivirus vectors were used to overexpress IGFBP3 in hepatocellular carcinoma cell (HCC) lines. The effect of IGFBP3 on proliferation was investigated by MTT and colony formation assays. Results: Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells. Conclusions: Expression of IGF2, IGFBP3, and PTEN in several HCC cell lines was lower than in normal cell lines. After 5-aza-2'-deoxycytidine/trichostatin A treatment, significant demethylation of the promoter region of IGFBP3 was observed in HCC cells. Overexpression of IGFBP3 induced apoptosis and reduced colony formation in HUH7 cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.6
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• pp.2655-2661
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• 2014

Background: Talin-1 is a cytoskeleton protein that participates in cell migration and plays a role in tumor formation, migration, and metastasis in different types of cancer. Chinese investigators have observed that the levels of Talin-1 protein and mRNA expression in HCC tissues are significantly lower than in the adjacent non-cancerous tissue. However, Japanese investigators have reported that Talin-1 is upregulated in HCC. Tln2 as homologous gene of Tln-1, which encodes a very similar protein, but the role of Talin-2 is very little known in primary liver cancer (PLC). We investigated whether the expression of Talin-1 in PLC may be associated with the histological subtype as well as the role of Talin-1 in tumor cell invasion and migration using human hepatocellular carcinoma cell lines. Materials and Methods: We measured the mRNA expression levels of Talin-1 and Talin-2 in five human liver cancer cell lines and normal human liver cell ($LO_2$ cell line) by real-time PCR and the protein expression levels of Talin-1 by Western blot. Migration and invasion of the cells were assessed using transwell assays and cell scratch experiments, respectively, and proliferation was assessed by soft AGAR colony formation. Results: Talin-1 and Talin-2 expression differed significantly between the five human liver cancer cell lines and $LO_2$ cell line (p<0.05). Compared with the $LO_2$ cell line, the invasion and migration capabilities of the five cancer cell lines differed significantly (p<0.05). Similarly, the colony-forming ability differed (p<0.05). Conclusions: High levels of Talin-1 expression are correlated with reduced invasion and migration as well as decreased malignancy in human liver cancer cell lines; the suppression of Talin-1 promotes invasion and migration. In addition, Talin-2 may be correlated with invasion and migration in human hepatocellular carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.2
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• pp.613-619
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• 2015

Background: Hepatocellular carcinoma (HCC) is the commonest primary malignant cancer of the liver in the world. Insulin-like growth factor-1 (IGF-1) levels reflect hepatic function and are inversely correlated with the severity of background chronic liver disease. Objective: This study evaluated whether basal serum IGF-1 levels can predict prognosis of HCC patients according to different risks of disease progression. Materials and Methods: A total of 89 patients with hepatocellular carcinoma (HCC) were recruited in 3 groups: Group I, 30 HCC patients receiving sorafinib; Group II, 30 HCC patients with best supportive care; and Group III include 29 patients undergoing transcatheter arterial chemoembolization (TACE). All patients were investigated for serum levels of AST, ALP, Bb, Cr, BUN, AFP and IGF-I. Results: Patients with disease control had significantly higher baseline IGF-1 levels 210 (185-232.5) ng/mL (p value<0.01) than did patients without disease control. Low basal IGF-1 levels were associated with advanced HCC, such as multiple tumors and advanced stage, and low IGF-1 levels predicted shorter TTP and overall survival in patients treated with TACE. Conclusions: The levels of serum IGF-1, expressed as continuous values, may be helpful for accurately assessing hepatic function and the prognostic stratification of patients with HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3741-3745
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• 2012

Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the most common form of liver cancer. However, while it is associated frequently with hepatitis C virus (HCV) there is only an elementary understanding of its molecular pathogenesis. Methods: To gain insight into the molecular mechanisms of HCV-induced hepatocarcinogenesis, we performed microarray analysis on 75 surgical liver samples from 48 HCV-infected patients. Results: There were 395 differentially expressed geness between cirrhotic samples and HCC samples. Of these, 125 genes were up-regulated and 270 genes were down-regulated. We performed pathway enrichment analysis and screened as described previously. Conclusions: The differentially expressed genes might be involved in hepatocarcinogenesis through upregulating the pathways of ECM-receptor interaction, focal adhesion, cell adhesion molecules and other cancer-related pathways, and downregulating the pathways of "complement and coagulation cascades". We hope our results could aid in seeking of therapeutic targets for HCV-induced hepatocellular carcinoma.

• Journal of Yeungnam Medical Science
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• v.29 no.1
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• pp.48-53
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• 2012

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in South Korea. To decrease its mortality rate, its early detection is very important. Screening for HCC detection has been accepted as the management modality for patients with chronic liver disease. Reported herein is a case involving the marked rapid growth of HCC detected at an advanced stage in a screening test with a 3 months interval. A 49-year-old male patient with chronic hepatitis B was admitted to the hospital due to a liver mass detected on CT scan. The patient underwent a first CT scan 3 months earlier, and no tumor was detected. Follow-up CT scan was performed and showed a 9.1 cm HCC with portal vein thrombosis. Percutaneous liver biopsy was performed, and the diagnosis of hepatocellular carcinoma was confirmed. In the pertinent guidelines, the recommended screening interval for HCC is 6-12 months, but the screening interval and additional diagnostic methods should be considered due to the variation in the HCC growth rate according to the patient's clinical characteristics.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.6159-6162
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• 2015

Purpose: To evaluate efficacy of transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) in treatment of patients with hepatocellular carcinoma. Materials and Methods: During January 2009 to March 2012, 80 patients with hepatocellular carcinoma underwent TACE, with or without RFA. Alfafetoprotein (AFP) was checked before and after procedure. CT scans were obtained one month after TACE or RFA for all patients to evaluate tumor changes. Complete response+partial response+stable disease (CR+PR+SD)/n were used to assess the disease control rate (DCR). Survival at 3, 6 and 12 months was compared in both groups. Results: AFP levels in TACE + RFA group dropped rapidly, becoming obviously lower than that of the TACE group. In the TACE + RFA group DCR was 93.8%, while only 76.8% in the TACE group. The treatment effect between the two groups was statistically significant (P<0.05) by Ridit analysis. 1 year survival rate in the TACE + RFA group was 92.5%, significantly higher than that of the TACE group at 77.5% (P<0.05). Conclusions: TACE and RFA as combined therapy method for patients with middle and terminal stage HCC gives full play to synergy between the two and improves the therapeutic effect.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5645-5650
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• 2013

Src homology 2 domain containing (SHC) is a proto-oncogene which mediates cell proliferation and carcinogenesis in human carcinomas. Here, the SHC SH2-domain binding protein 1 (SHCBP1) was first established to be up-regulated in human hepatocellular carcinoma (HCC) tissues by array-base comparative genome hybridization (aCGH). Meanwhile, we examine and verify it by quantitative real-time PCR and western blot. Our current data show that SHCBP1 was up-regulated in HCC tissues. Overexpression of SHCBP1 could significantly promote HCC cell proliferation, survival and colony formation in HCC cell lines. Furthermore, knockdown of SHCBP1 induced cell cycle delay and suppressed cell proliferation. Furthermore, SHCBP1 could regulate the expression of activate extracellular signal-regulated kinase 1/2 (ERK1/2) and cyclin D1. Together, our findings indicate that SHCBP1 may contribute to human hepatocellular carcinoma by promoting cell proliferation and may serve as a molecular target of cancer therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3289-3294
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• 2016

Naringin, a bioflavonoid found in Citrus seeds, inhibits proliferation of cancer cells. The objectives of this study were to investigate the mode and mechanism(s) of hepatocellular carcinoma HepG2 cell death induced by naringin. The cytotoxicity of naringin towards HepG2 cells proved dose-dependent, measured by MTT assay. Naringin-treated HepG2 cells underwent apoptosis also in a concentration related manner, determined by annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) employing flow cytometry. Mitochondrial transmembrane potential (MTP) measured using 3,3'-dihexyloxacarbocyanine iodide ($DiOC_6$) and flow cytometer was reduced concentration-dependently, which indicated influence on the mitochondrial signaling pathway. Caspase-3, -8 and -9 activities were enhanced as evidenced by colorimetric detection of para-nitroaniline tagged with a substrate for each caspase. Thus, the extrinsic and intrinsic pathways were linked in human naringin-treated HepG2 cell apoptosis. The expression levels of pro-apoptotic Bax and Bak proteins were increased whereas that of the anti-apoptotic Bcl-xL protein was decreased, confirming the involvement of the mitochondrial pathway by immunoblotting. There was an increased expression of truncated Bid (tBid), which indicated caspase-8 proteolysis activity in Bid cleavage as its substrate in the extrinsic pathway. In conclusion, naringin induces human hepatocellular carcinoma HepG2 cell apoptosis via mitochondria-mediated activation of caspase-9 and caspase-8-mediated proteolysis of Bid. Naringin anticancer activity warrants further investigation for application in medical treatment.

• THE JOURNAL OF KOREAN ORIENTAL ONCOLOGY
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• v.7 no.1
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• pp.117-129
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• 2001

Objectives: We compared the therapeutic response, the treatment-related toxicity, and the improvement of subjective symptoms between the chemotherapy alone group and the western-oriental combined treatment group and evaluated the role of oriental medicine for the improvement of chemotherapy-related toxicity in the advanced gastric cancer and hepatocellular carcinoma. Methods: We evaluated 36 gastric cancer or hepatocellular carcinoma patients(chemotherapy alone group 25 patients, combined treatment group 11 patients) who had been treated in Wonju Christian Hospital and Hana Hospital of Oriental Medicine between June 1999 and October 2000. Enrolled patients' general medical records, results of laboratory and imaging studies, treatment-related toxicities, and subjective symptoms were recorded regularly according to the planned protocol. Therapeutic responses were estimated according to the WHO response criteria and the changes of tumor marker value such as CEA, CA 72-4 and AFP. Results: 1. There was no significant difference of therapeutic response by the WHO response criteria between the two groups(p=.459). 2. There was a significant decrease of tumor marker value in the combined treatment group compared to the chemotherapy alone group(p=.023). 3. There was less comprehensive treatment-related toxicity in the combined treatment group compared to the chemotherapy alone group(p=.037), but there was not a significant difference of comprehensive improvement of subjective symptoms between the two groups(p=.091). Conclusions: Based on the above results, we could expect the possibility of improvements in therapeutic response and treatment-related toxicity with the western-oriental combined anticancer treatment.