• BMB Reports
• /
• 제52권4호
• /
• pp.277-282
• /
• 2019

Currently speaking, it is noted that radiofrequency ablation (RFA) has been the most widely used treatment for hepatocellular carcinoma (HCC) occurring in patients. However, accumulating evidence has demonstrated that the incidence of insufficient RFA (IRFA) may result in the identified rapid progression of residual HCC in the patient, which can greatly hinder the effectiveness and patient reported benefits of utilizing this technique. Although many efforts have been proposed, the underlying mechanisms triggering the rapid progression of residual HCC after IRFA have not yet been fully clarified through current research literature reviews. It was shown in this study that cell proliferation, migration and invasion of residual HepG2 and SMMC7721 cells were significantly increased after the IRFA was simulated in vitro. In other words, it is noted that IRFA could do this by enhancing the image of autophagy of the residual HCC cell via the $HIF-1{\alpha}/BNIP3$ pathway. Consequently, the down-regulation of BNIP3 may result in the inhibition of the residual HCC cell progression and autophagy after IRFA. Our present study results suggest that IRFA could promote residual HCC cell progression in vitro by enhancing autophagy via the $HIF-1{\alpha}/BNIP3$ pathway. For this reason, it is noted that the targeting of the BNIP3 may be useful in preventing the rapid growth and metastasis of residual HCC after IRFA.

• 한국임상약학회지
• /
• 제31권2호
• /
• pp.153-159
• /
• 2021

Background: With increasing economic evaluation studies on the treatment of or screening tools for liver diseases that cause hepatocellular carcinoma (HCC), interest in the analysis of the medical utilization and costs of HCC treatment is increasing. Therefore, we aimed to estimate the medical utilization and costs of HCC patients, and calculate the cost of main procedures for HCC treatment, including liver transplant (LT), hepatic resection (HR), radiofrequency ablation (RFA), and transarterial chemoembolization (TACE). Methods: We analyzed claim data from January to December 2018 from the Health Insurance and Review and Assessment Service-National Patient Sample (HIRA-NPS-2018) dataset, including data of patients diagnosed with HCC (Korean Standard Classification of Diseases code C22.0) who had at least one inpatient claim for HCC. Results: A total of 715 HCC patients were identified. In 2018, the yearly average medical cost per HCC patient was ₩18,460K (thousand), of which ₩14,870K was attributed to HCC. Among the total medical costs of HCC patients, the inpatient cost accounted for the largest portion of both the total medical and HCC-related costs. The major procedures of HCC treatment occurred most frequently in the order of TACE, RFA, HR, and LT. The average medical cost per treatment episode was the highest for LT (₩87,280K), followed by HR (₩10,026K), TACE (₩4,047K), and RFA (₩2,927K). Conclusion: By identifying the medical costs of HCC patients and the costs of the main procedures of HCC treatment, our results provide basic information that could be utilized for cost estimation in liver disease-related economic evaluation studies.

• The Korean Journal of Physiology and Pharmacology
• /
• 제26권6호
• /
• pp.457-468
• /
• 2022

It has been demonstrated that APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) is involved in the regulation of several growth-related signaling pathways and thus closely associated with the development and progression of some cancers. Diallyl trisulfide (DAT), a garlic-derived bioactive compound, exerts selective cytotoxicity to various human cancer cells through interfering with pro-survival signaling pathways. However, whether and how DAT affects survival of human hepatocellular carcinoma (HCC) cells remain unclear. Herein, we tested the hypothesis of the involvement of APPL1 in DAT-induced cytotoxicity in HCC HepG2 cells. We found that Lys 63 (K63)-linked polyubiquitination of APPL1 was significantly decreased whereas phosphorylation of APPL1 at serine residues remained unchanged in DAT-treated HepG2 cells. Compared with wild-type APPL1, overexpression of APPL1 K63R mutant dramatically increased cell apoptosis and mitigated cell survival, along with a reduction of phosphorylation of STAT3, Akt, and Erk1/2. In addition, DAT administration markedly reduced protein levels of intracellular TNF receptor-associated factor 6 (TRAF6). Genetic inhibition of TRAF6 decreased K63-linked polyubiquitination of APPL1. Moreover, the cytotoxicity impacts of DAT on HepG2 cells were greatly attenuated by overexpression of wild-type APPL1. Taken together, these results suggest that APPL1 polyubiquitination probably mediates the inhibitory effects of DAT on survival of HepG2 cells by modulating STAT3, Akt, and Erk1/2 pathways.

• BMB Reports
• /
• 제55권11호
• /
• pp.547-552
• /
• 2022

Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib.

• 대한한의학방제학회지
• /
• 제30권2호
• /
• pp.67-83
• /
• 2022

Objectives : In this study, the anticancer activity of water extracts of three herbal medicine formulas, Bigihwan (BGH), Daechilgitang (DCGT) and Mokwhyangbinranghwan (MHBRH) listed in Donguibogam, was evaluated in HepG2 cells, a human hepatocellular carcinoma cell line. Methods : We investigated whether the cell viability of HepG2 cells was inhibited by the treatment of water extracts of three prescriptions, and whether their viability inhibitory effect was related to the induction of apoptosis. In addition, the role of autophagy on the induction of apoptosis by the treatment of these extracts was investigated. Results : The anticancer activity of the three water extracts on HepG2 cells was due to induction of apoptosis, not necrosis. Among them, BGH activated the caspase-dependent intrinsic apoptosis pathway associated with mitochondrial dysfunction. However, autophagy was induced more than 2-fold in DCGT-treated HepG2 cells, and the anticancer activity of DCGT was enhanced 1.5-fold in the presence of an autophagy inhibitor, but was attenuated in BGH and MHBRH-treated cells. Conclusion : The results of this study indicate that DCGT-induced autophagy was involved in the inhibition of apoptosis, whereas autophagy by BGH and MHBRH was related to induction of apoptosis.

• Molecules and Cells
• /
• 제45권8호
• /
• pp.550-563
• /
• 2022

Hepatocellular carcinoma (HCC) is an aggressive and incurable cancer. Although understanding of the molecular pathogenesis of HCC has greatly advanced, therapeutic options for the disease remain limited. In this study, we demonstrated that SETD5 expression is positively associated with poor prognosis of HCC and that SETD5 depletion decreased HCC cell proliferation and invasion while inducing cell death. Transcriptome analysis revealed that SETD5 loss downregulated the interferon-mediated inflammatory response in HCC cells. In addition, SETD5 depletion downregulated the expression of a critical glycolysis gene, PKM (pyruvate kinase M1/2), and decreased glycolysis activity in HCC cells. Finally, SETD5 knockdown inhibited tumor growth in xenograft mouse models. These results collectively suggest that SETD5 is involved in the tumorigenic features of HCC cells and that targeting SETD5 may suppress HCC progression.

• BMB Reports
• /
• 제55권10호
• /
• pp.506-511
• /
• 2022

Advanced hepatocellular carcinoma (HCC) is among the most challenging cancers to overcome, and there is a need for better therapeutic strategies. Among the different cancer drugs that have been used in clinics, sorafenib is considered the standard first-line drug for advanced HCC. Here, to identify a chemical compound displaying a synergistic effect with sorafenib in HCC, we screened a focused chemical library and found that MG149, a histone acetyltransferase inhibitor targeting the MYST family, exhibited the most synergistic anticancer effect with sorafenib on HCC cells. The combination of sorafenib and MG149 exerted a synergistic anti-proliferation effect on HCC cells by inducing apoptotic cell death. We revealed that cotreatment with sorafenib and MG149 aggravated endoplasmic reticulum (ER) stress to promote the death of HCC cells rather than adaptive cell survival. In addition, combined treatment with sorafenib and MG149 significantly increased the intracellular levels of unfolded proteins and reactive oxygen species, which upregulated ER stress. Collectively, these results suggest that MG149 has the potential to improve the efficacy of sorafenib in advanced HCC via the upregulation of cytotoxic ER stress.

• Journal of Microbiology and Biotechnology
• /
• 제33권7호
• /
• pp.864-874
• /
• 2023

Natural killer (NK) cell dysfunctions against hepatocellular carcinoma (HCC) in a hypoxic environment. Many solid tumors are present in a hypoxic condition, which changes the effector function of various immune cells. The transcription of hypoxic-inducible factors (HIFs) in cancer cells make it possible to adapt to their hypoxic environment and to escape the immune surveillance of NK cells. Recently, the correlation between the transcription of HIF-1α and pro-inflammatory cytokines has been reported. Interleukin (IL)-6 is higher in cancers with a highly invasive ability, and is closely related to the metastasis of cancers. This study showed that the expression of HIF-1α in HCC cells was associated with the presence of IL-6 in the environment of HCC-NK cells. Blocking of IL-6 by antibody in the HCC-NK interaction changed the production of several cytokines including TGF-β, IL-1, IL-18 and IL-21. Interestingly, in a co-culture of HIF-1α-expressed HCC cells and NK cells, blocking of IL-6 increased the production of IL-21 in their supernatants. In addition, the absence of IL-6 significantly enhanced the cytotoxic ability and the expression of the activating receptors (NKG2D, NKp44, and NKG2C) in NK cells to HIF-1α-expressed HCC cells. These effects might be made by the decreased expression of HIF-1α in HCC cells through the inhibited phosphorylation of STAT3. In conclusion, the absence of IL-6 in the interaction of HIF-1α-expressed HCC cells and NK cells could enhance the antitumor activity of NK cells to HCC cells.

• 대한통합의학회지
• /
• 제11권3호
• /
• pp.59-67
• /
• 2023

Purpose : Epithelial-to-mesenchymal transition (EMT) is recognized as an important cellular response in metastatic proceduresand characterized by loss of cellular polarity as well as gain of mesenchymal features, which enables migration and invasion. Hepatocellular carcinoma (HCC) is one of the most common primary carcinomas in the liver and exhibits a poor prognosis due to frequent extrahepatic metastasis. Taraxacum officinale has been used for a long time in oriental medicine because of its various pharmacological activitiessuch as anti-rheumatic, anti-inflammatory, antioxidative, and anticarcinogenic activities. In this study, the anti-metastatic activity of T. officinale water extract (TOWE) and ethanol extract (TOEE) was investigated through the regulation of EMT in the Huh7 cells. Methods : The effects of TOWE and TOEE on migratory and invasive activities were investigated by wound healing and in vitro invasion assays. Western blot analysis was also applied to analyze protein expression levels associated with EMT and their upstream transcription factors in Huh7 cells. Results : TOWE and TOEE treatment potently inhibited migration and invasion of Huh7 cells compared to the untreated group. Both extracts treatment inhibited protein expression levels of N-cadherin, matrix metalloproteinase (MMP)-9, and vimentin while E-cadherin was significantly accelerated. In addition, the activated status of transcription factors, Snail, nuclear factor (NF)-κ B, and zinc finger E-box binding homeobox (ZEB)1 was also inhibited with statistical significance. In comparison to both extracts, TOEE more potently attenuated migration, invasion, and EMT markers as well as their transcription factors in Huh7 cells than TOWE, which means that TOEE might possess more functional phytochemicals than TOWE. Conclusion : Consequently, TOWE and TOEEattenuated metastatic activity of hepatocellular carcinoma through the regulation of EMT markers and their transcription factors in Huh7 cells, which means that T. officinale might be a promising strategy for a chemopreventive agent against HCC metastasis.

• 대한의생명과학회지
• /
• 제29권1호
• /
• pp.11-25
• /
• 2023

In hepatocellular carcinoma (HCC), chromosome 4 open-reading frame 47 (C4orf47) has not been so far investigated for its prognostic value or association with infiltrating immune cells. We performed bioinformatics analysis on HCC data and analyzed the data using online databases such as TIMER, UALCAN, Kaplan-Meier plotter, LinkedOmics, and GEPIA2. We found that C4orf47 expression in HCC was higher compared to normal tissues. High C4orf47 expression was associated with a worse prognosis in HCC. The correlation between C4orf47 and infiltrating immune cells is positively associated with CD4+T cells, B cells, neutrophils, macrophages, and dendritic cells in HCC. Moreover, high C4orf47 expression was correlated with a poor prognosis of infiltrating immune cells. Analysis of C4orf47 gene co-expression networks revealed that 12501 genes were positively correlated with C4orf47, whereas 7200 genes were negatively correlated. The positively related genes of C4orf47 are associated with a high hazard ratio in different types of cancer, including HCC. Regarding the biological functions of C4orf47 gene, it mainly regulates RNA metabolic process, DNA replication, and cell cycle. The C4orf47 gene may play a prognostic role by regulating the global transcriptome process in HCC. Our findings demonstrate that high C4orf47 expression correlates with poor prognosis and tumor-infiltrating immune cells in HCC. We suggest that C4orf47 is a novel prognostic biomarker and potential immune therapeutic target for HCC.