• Biomolecules & Therapeutics
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• v.31 no.2
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• pp.200-209
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• 2023

Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) amplification or sensitive mutations initially respond to the tyrosine kinase inhibitor gefitinib, however, the treatment becomes less effective over time by resistance mechanism including mesenchymal-epithelial transition (MET) overexpression. A therapeutic strategy targeting MET and EGFR may be a means to overcoming resistance to gefitinib. In the present study, we found that picropodophyllotoxin (PPT), derived from the roots of Podophyllum hexandrum, inhibited both EGFR and MET in NSCLC cells. The antitumor efficacy of PPT in gefitinib-resistant NSCLC cells (HCC827GR), was confirmed by suppression of cell proliferation and anchorage-independent colony growth. In the targeting of EGFR and MET, PPT bound with EGFR and MET, ex vivo, and blocked both kinases activity. The binding sites between PPT and EGFR or MET in the computational docking model were predicted at Gly772/Met769 and Arg1086/Tyr1230 of each ATP-binding pocket, respectively. PPT treatment of HCC827GR cells increased the number of annexin V-positive and subG1 cells. PPT also caused G2/M cell-cycle arrest together with related protein regulation. The inhibition of EGFR and MET by PPT treatment led to decreases in the phosphorylation of the downstream-proteins, AKT and ERK. In addition, PPT induced reactive oxygen species (ROS) production and GRP78, CHOP, DR5, and DR4 expression, mitochondrial dysfunction, and regulated involving signal-proteins. Taken together, PPT alleviated gefitinib-resistant NSCLC cell growth and induced apoptosis by reducing EGFR and MET activity. Therefore, our results suggest that PPT can be a promising therapeutic agent for gefitinib-resistant NSCLC.

• Journal of The Korean Society of Integrative Medicine
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• v.11 no.3
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• pp.59-67
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• 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.

• Korean Journal of Plant Resources
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• v.36 no.3
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• pp.207-218
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• 2023

Hepatocellular carcinoma (HCC) has a poor prognosis and high metastasis and recurrence rates. Although extracts of Alnus hirsuta (Turcz. ex Spach) Rupr. (AH) have been demonstrated to possess potential anti-inflammatory and anti-cancer activities, the underlying mechanism of AH in HCC treatment remains to be elucidated. We investigated the effects and potential mechanisms of AH on migration and invasion of Hep3B cells. Within the non-cytotoxic concentration range, AH significantly inhibited motility and invasiveness of Hep3B cells in a concentration-dependent manner. Inhibitory effects of AH on cell invasiveness are associated with tightening of tight junctions (TJs), as demonstrated by an increase in transepithelial electrical resistance. Immunoblotting indicated that AH decreased levels of claudins, which form major components of TJs and play key roles in the control and selectivity of paracellular transport. Furthermore, AH inhibited the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and simultaneously increased the levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These effects were related to inactivation of the phosphoinositide 3-kinase (PI3K)/AKT pathway in Hep3B cells. Therefore, AH inhibits migration and invasion of Hep3B cells by inhibiting the activity of MMPs and tightening TJs through suppression of claudin expression, possibly by suppressing the PI3K/AKT signaling pathway.

• Korean Journal of Radiology
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• v.22 no.8
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• pp.1279-1288
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• 2021

Objective: To assess the diagnostic performance of the Liver Imaging Reporting and Data System (LI-RADS) version 2018 treatment response algorithm (TRA) for the evaluation of hepatocellular carcinoma (HCC) treated with transarterial radioembolization. Materials and Methods: This retrospective study included patients who underwent transarterial radioembolization for HCC followed by hepatic surgery between January 2011 and December 2019. The resected lesions were determined to have either complete (100%) or incomplete (< 100%) necrosis based on histopathology. Three radiologists independently reviewed the CT or MR images of pre- and post-treatment lesions and assigned categories based on the LI-RADS version 2018 and the TRA, respectively. Diagnostic performances of LI-RADS treatment response (LR-TR) viable and nonviable categories were assessed for each reader, using histopathology from hepatic surgeries as a reference standard. Inter-reader agreements were evaluated using Fleiss κ. Results: A total of 27 patients (mean age ± standard deviation, 55.9 ± 9.1 years; 24 male) with 34 lesions (15 with complete necrosis and 19 with incomplete necrosis on histopathology) were included. To predict complete necrosis, the LR-TR nonviable category had a sensitivity of 73.3-80.0% and a specificity of 78.9-89.5%. For predicting incomplete necrosis, the LR-TR viable category had a sensitivity of 73.7-79.0% and a specificity of 93.3-100%. Five (14.7%) of 34 treated lesions were categorized as LR-TR equivocal by consensus, with two of the five lesions demonstrating incomplete necrosis. Interreader agreement for the LR-TR category was 0.81 (95% confidence interval: 0.66-0.96). Conclusion: The LI-RADS version 2018 TRA can be used to predict the histopathologic viability of HCCs treated with transarterial radioembolization.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1589-1593
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• 2012

Objective: To investigate liver fibrosis, TGF-${\beta}1$ levels and curative effects on hepatocellular carcinoma (HCC) with small and conventional dose perfusion chemotherapy by transcatheter arterial chemo embolization (TACE). Methods: Thirty-six hepatocellular carcinoma patients not indicated for surgical resection underwent super-selective transcatheter arterial chemoembolization, divided into small dose (n=15) and conventional dose (n=21) chemotherapy groups. Results: With conventional doses, four indices of liver fibrosis focusing on hyaluronate acide (HA), human procollagen type-III (hPC-III), collagen type-Ⅳ (Ⅳ-C) and transforming growth factor-${\beta}l$ (TGF-${\beta}1$) were obviously increased postoperative compared with preoperative (P<0.01); in contrast, with small doses there were no significant differences except for TGF-${\beta}1$. Five year survival demonstrated no significant differences between the two groups (P>0.05). Conclusion: To hepatocellular carcinoma patients treated by TACE, reducing doses of chemotherapy drugs can reduce progress of liver fibrosis, without impacting on five year survival.

• Biomedical Science Letters
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• v.18 no.4
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• pp.435-437
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• 2012

House dust mite (HDM) is important in the pathogenesis of allergic diseases including asthma and atopic dermatitis. Dermatophagoides pteronissinus (Dp) is one of major HDM allergens. In this study, we investigated that Dp extract (DpE) affects on the chemotactic activity of monocytes isolated from the peripheral blood. DpE inhibited the migration of human monocytes in response to CC chemokines such as MIP-$1{\alpha}$, RANTES, HCC-4, MCP-1, and TARC. DpE did not alter the expression of CC chemokine receptors (CCRs) such as CCR1, CCR2, CCR3, CCR4, and CCR5. These results indicate that DpE blocks the chemotaxis of human monocytes and its mechanism is not involved in alteration of CCR expression. Better understanding of the effect of DpE on monocytes will enable elucidation of the role of Dp in the development of allergic diseases.

• Journal of Chest Surgery
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• v.42 no.2
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• pp.141-147
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• 2009

Background: We performed this study to identify the tumor suppressor genes located in the long arm of chromosome 21 in non-small cell lung cancer. Material and Method: The genes of USP25 in 21q11.2, NCAM2, ADAMTS1 in 21q21.2, and Claudin-8 (CLDN8), Claudin-17 (CLDN17) and TIAM1 in 21q22.1 were investigated for their gene expressions, genetic alterations and promoter methylation. Result: The expressions of CLDN8 and CLDN17 were significantly decreased in 7 (L132, H157, H358, H522, H1299, H1703 and HCC2108) of 13 cell lines, and the expression of ADAMTS1 was also significantly reduced in 6 cell lines (A549, SW900, H1299, H1373, H1703 and H1793). There were no genetic alterations by PCR-SSCP and cDNA cloning in the cell lines with a decreased gene. In the cell lines with a decreased gene expression, the mRNA expression was increased significantly with treatment of 5-Aza-CdR. Conclusion: These results suggest that the ADMTS1, CLDN8 and CLDN17 may act as tumor suppressor genes.

• Journal of Electrical Engineering and Technology
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• v.13 no.1
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• pp.270-279
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• 2018

This paper elucidates a hysteresis current controller for enhancing the performance of static synchronous compensator (STATCOM) using cascaded H-bridge multilevel inverter. Due to the rising power demand and growing conventional generation costs a new alternative in renewable energy source is gaining popularity and recognition. A five level single phase cascaded multilevel inverter with two separated dc sources, which is energized by photovoltaic - wind hybrid energy source. The voltages across the each dc source is balanced and standardized by the proposed hysteresis current controller. The performance of STATCOM is analyzed by connecting with grid connected system, under the steady state & dynamic state. To reduce the Total Harmonic Distortion (THD) and to improve the output voltage, closed loop hysteresis current control is achieved using PLL and PI controller. The performance of the proposed system is scrutinized through various simulation results using matlab/simulink and hardware results are also verified with simulation results.

• Radiation Oncology Journal
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• v.25 no.3
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• pp.170-176
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• 2007

Purpose: To determine the role of radiotherapy for the treatment of portal vein thrombosis (PVT) from hepatocellular carcinoma (HCC). Material and Methods: A retrospective analysis was performed on 70 patients that had been diagnosed with HCC and were treated with three-dimensional conformal radiotherapy (3D-CRT) for the PVT. The radiation dose ranged from 40 Gy to 60 Gy (median dose: 48 Gy) and the biological effective dose (BED) ranged from 31.3 Gy to 78.0 $Gy_{10}$ (median dose: 61.6 $Gy_{10}$). Response was determined by measuring the extent of the PVT on a CT image at 0, 1 and 3 months after completion of the radiotherapy. The median follow-up period was 9 months. Results: The response rate was 47.1% (33 patients), with two patients (2.9%) showing a complete response, 31 patients (44.3%) showing a partial response, and 35 patients (50%) showing stable disease or no response. The 1-year progression-free survival rate was 60%, and the median progression-free survival time was 17 months. The median overall survival time was 11 months, the median survival time in the responders was 15 months and in the nonresponders was 8 months (p=0.032). Four patients (5.7%) had transient liver function impairment during treatment. Radiation induced liver disease (RILD) was observed in only one patient (1.4%). Conclusion: Three-dimensional conformal radiotherapy for the treatment of PVT from advanced HCC was a relatively effective and safe method.

• Journal of Life Science
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• v.32 no.2
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• pp.94-100
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• 2022

Chronic infection by hepatitis B virus (HBV) greatly increases the risk for liver cirrhosis and hepatocellular carcinoma (HCC). The outcome of HBV infection is shaped by the complex interplay of the mode of transmission, host genetic factors, viral genotype, adaptive mutations, and environmental factors. The pregenomic RNA transcription of HBV for their replication is regulated by the core promoter activation. Core promoter mutations have been the reason for acute liver failure and are associated with HCC development. We obtained HBV genes from a patient in Myanmar who was infected with HBV and identified gene variations in the core promoter region. For measuring the relative transactivation activity of the core promoter, we prepared the core-promoter reporter construct. Among the gene variations of the core promoter, the mutations of C1731T and G1806A were associated with increase in the transactivation of the HBV core promoter. Through computer analysis for searching for a tentative transcription factor binding site, we showed that the mutations of C1713T and G1806A newly created C/EBPβ and XBP1-responsive elements of the core promoter, respectively. The ectopic expression of C/EBPβ largely increased the HBV core promoter containing the C1713T mutation and that of XBP1 activated the M95 promoter containing the G1806A mutation. Our efforts to treat and prevent HBV infections are hampered by the emergence of drug-resistant mutations and vaccine-escape mutations. Our results provide the biological properties and clinical significance of specific HBV core promoter mutations.