• BMB Reports
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• v.52 no.3
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• pp.208-213
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• 2019

Chemoresistance is the primary obstacle in the treatment of locally advanced and metastatic nasopharyngeal carcinoma (NPC). Recent evidence suggests that the transcription factor forkhead box M1 (FoxM1) is involved in chemoresistance. Our group previously confirmed that FoxM1 is overexpressed in NPC. In this study, we investigated the role of FoxM1 in cisplatin resistance of the cell lines 5-8F and HONE-1 and explored its possible mechanism. Our results showed that FoxM1 and NBS1 were both overexpressed in NPC tissues based on data from the GSE cohort (GSE12452). Then, we measured FoxM1 levels in NPC cells and found FoxM1 was overexpressed in NPC cell lines and could be stimulated by cisplatin. MTT and clonogenic assays, flow cytometry, ${\gamma}H2AX$ immunofluorescence, qRT-PCR, and western blotting revealed that downregulation of FoxM1 sensitized NPC cells to cisplatin and reduced the repair of cisplatin-induced DNA double-strand breaks via inhibition of the MRN (MRE11-RAD50-NBS1)-ATM axis, which might be related to the ability of FoxM1 to regulate NBS1. Subsequently, we demonstrated that enhanced sensitivity of FoxM1 knockdown cells could be reduced by overexpression of NBS1. Taken together, our data demonstrate that downregulation of FoxM1 could improve the sensitivity of NPC cells to cisplatin through inhibition of MRN-ATM-mediated DNA repair, which could be related to FoxM1-dependent regulation of NBS1.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.28 no.3
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• pp.193-201
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• 2006

Squamous cell carcinoma(SCC) of head and neck(SCCHN) is the sixth most common human malignant tumor. However, despite advances in prevention and treatment of SCC, the five-year survival rates for patients remain still low. To improve the outcome for patients with SCCHN, novel treatment strategies are needed. Overexpression of the epidermal growth factor(EGF) and activation of its receptor(EGFR) are associated with progressive growth of SCCHN. Vascular endothelial growth factor(VEGF) signaling molecules are related with neoangiogenesis and vascular metastasis of SCC. In this study, we determined the therapeutic effect of AEE788(Novartis Pharma AG, Basel, Switzerland), which is a dual inhibitor of EGFR/ErbB2 and VEGFR tyrosine kinases, on human oral SCC. At first, we screened the expression of EGFR, c-ErbB2(HER-2) and VEGFR-2 in a series of human oral SCC cell lines. And then we evaluated the effects of AEE788 on the phosphorylation of EGFR and VEGFR-2 in a oral SCC cell line expressing EGFR/HER-2 and VEGFR-2. We also evaluated the effects of AEE788 alone, or with paclitaxel(Taxol) on the oral SCC cell growth and apoptosis. As a result, all oral SCC cells expressed EGFR and VEGFR-2. Treatment of oral SCC cells with AEE788 led to dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation, growth inhibition, and induction of apoptosis. Moreover, AEE788 sensitizes the cells to paclitaxel-mediated toxicity and apoptosis. These data mean EGFR and VEGFR-2 can be reliable targets for molecular therapy of oral SCC, and therefore warrant clinical use of EGFR/VEGFR inhibition in the treatment of patients with recurrent or metastatic oral SCC.

• Journal of Gastric Cancer
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• v.20 no.1
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• pp.95-105
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• 2020

Purpose: Gastric cancer is a highly metastatic malignant tumor, often characterized by chemoresistance and high mortality. In the present study, we aimed to investigate the role of B-cell lymphoma 3 (Bcl-3) protein on cell migration and chemosensitivity of gastric cancer. Materials and Methods: The gastric cancer cell lines, AGS and NCI-N87, were used for the in vitro studies and the in vivo studies were performed using BALB/c nude mice. Western blotting, wound healing assay, Cell Counting Kit-8 assay, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay were used to evaluate the role of Bcl-3 in gastric cancer. Results: We found that the protein expression of hypoxia (HYP)-inducible factor-1α and Bcl-3 were markedly upregulated under hypoxic conditions in both AGS and NCI-N87 cells in a time-dependent manner. Interestingly, small interfering RNA-mediated knockdown of Bcl-3 expression affected the migration and chemosensitivity of the gastric cancer cells. AGS and NCI-N87 cells transfected with si-RNA-Bcl-3 (si-Bcl-3) showed significantly reduced migratory ability and increased chemosensitivity to oxaliplatin, 5-fluorouracil, and irinotecan. In addition, si-Bcl-3 restored the autophagy induced by HYP. Further, the protective role of si-Bcl-3 on the gastric cancer cells could be reversed by the autophagy inducer, rapamycin. Importantly, the in vivo xenograft tumor experiments showed similar results. Conclusions: Our present study reveals that Bcl-3 knockdown inhibits cell migration and chemoresistance of gastric cancer cells through restoring HYP-induced autophagy.

• The Journal of the Korean bone and joint tumor society
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• v.4 no.1
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• pp.13-21
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• 1998

Taxol, the extract from the Taxus brevifolia which is a Pacific yew tree has aroused the interest of the tumor investigators since the 1960s. As well, it is shown to have broad antitumor activity in preclinical experimental models. Its action mechanism is an anti-microtubule effect by duplication of tubulin. The most impressive antitumor activity of taxol has been observed in advanced ovarian cancer and metastatic breast cancer. The purpose of this study was to determine how taxol acts on malignant bone tumor cell lines, to compare its cytotoxic effect with those of other chemotherapeutic agents, and to ascertain the its combination effect with adriamycin. Cell lines used in this study were G-292(osteosarcoma, human), SaOS-2(osteosarcoma, primary, human), and HT-1080(fibrosarcoma, human). Methotrexate, adriamycin, cisplatinum, ifosfamide and taxol were used as testing chemotherapeutic agents and their maximum test concentration were $500{\mu}g/ml$, $200{\mu}g/ml$, $500{\mu}g/ml$, $1000{\mu}g/ml$, and $600{\mu}g/ml$, respectively. The media for cell culture was RPMI-1640 with 10% fetal bovine serum and gentamycin. The results were as follows. The $IC_{50}$ of methotrexate, ifosfamide, cisplatinum, adriamycin and Taxol in G-292 were $2.3{\times}10^{-1}{\mu}g/ml$, $8.0{\times}10^0{\mu}g/ml$, $3.5{\times}10^0{\mu}g/ml$, $9.8{\times}10^{-1}{\mu}g/ml$, $2.7{\times}10^{-2}{\mu}g/ml$ respectively, in SaOS-2 $3.5{\times}10^{-1}{\mu}g/ml$, $1.5{\times}10^1{\mu}g/ml$, $2.8{\times}10^0{\mu}g/ml$, $9.9{\times}10^{-2}{\mu}g/ml$, $1.0{\times}10^{-2}{\mu}g/ml$, respectively, in HT-1080 $4.2{\times}10^{-2}{\mu}g/ml$, $5.4{\times}10^1{\mu}g/ml$, $3.8{\times}10^0{\mu}g/ml$, $5.5{\times}10^{-3}{\mu}g/ml$, $1.1{\times}10^{-3}{\mu}g/ml$, respectively. In conclusion, taxol had very potent cytotoxic effect on the malignant bone tumor cell lines with adriamycin, and was more potent than methotrexate, cisplatinum and ifosfamide. There were synergistic antitumor effects on G-292 and SaOS-2 cell lines in combination test of taxol and adriamycin. From the above results, it would be estimated that taxol could be a new antitumor drug for the malignant bone tumors, providing measures against the side effects and followed by the clinical tests.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.3
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• pp.1031-1038
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• 2012

Background: Turmeric ($Curcuma$ $longa$) has been shown to possess anti-inflammatory, antioxidant and antitumor properties. However, despite the progress in research with $C.$ $longa$, there is still a big lacuna in the information on the active principles and their molecular targets. More particularly very little is known about the role of cell cycle genes $p57^{kip2}$ and Rad9 during chemoprevention by turmeric and its derivatives especially in prostate cancer cell lines. Methods: Accordingly, in this study, we have examined the antitumor effect of several extracts of $C.$ $longa$ rhizomes by successive fractionation in clonogenic assays using highly metastatic PC-3M prostate cancer cell line. Results: A mixture of isopropyl alcohol: acetone: water: chloroform: and methanol extract of $C.$ $longa$ showed significant bioactivity. Further partition of this extract showed that bioactivity resides in the dichloromethane soluble fraction. Column chromatography of this fraction showed presence of biological activity only in ethyl acetate eluted fraction. HPLC, UV-Vis and Mass spectra studies showed presence three curcuminoids in this fraction besides few unidentified components. Conclusions: From these observations it was concluded that the ethyl acetate fraction showed not only inhibition of colony forming ability of PC-3M cells but also up-regulated cell cycle genes $p57^{kip2}$ and Rad9 and further reduced the migration and invasive ability of prostate cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.15
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• pp.6359-6364
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• 2015

Background: Preclinical studies have shown that the combination of an aromatase inhibitor (AI) and capecitabine in estrogen receptor (ER)- positive cell lines enhance antitumor efficacy. This retrospective analysis of a group of patients with metastatic breast cancer (MBC) evaluated the efficacy and safety of combined AI with capecitabine. Materials and Methods: Patients with hormone receptor-positive metastatic breast cancer treated between 1st January 2005 and 31st December 2010 with a combination of capecitabine and AI were evaluated and outcomes were compared with those of women treated with capecitabine in conventional dose or AI as a monotherapy. Results: Of 72 patients evaluated, 31 received the combination treatment, 22 AI and 19 capecitabine. The combination was used in 20 patients as first-line and 11 as second-line treatment. Mean age was 46.2 years with a range of 28-72 years. At the time of progression, 97% had a performance status of <2 and 55% had visceral disease. No significant difference was observed between the three groups according to clinical and pathological features. Mean follow up was 38 months with a range of 16-66 months. The median PFS of first-line treatment was significantly better for the combination (PFS 21 months vs 8.0 months for capecitabine and 15.0 months for AI). For second-line treatment, the PFS was longer in the combination compared with capecitabine and Al groups (18 months vs. 5.0 months vs. 11.0 months, respectively). Median 2 year and 5 year survival did not show any significant differences among combination and monotherapy groups. The most common adverse events for the combination group were grade 1 and 2 hand-for syndrome (69%), grade 1 fatigue (64%) and grade 1 diarrhoea (29%). Three grade 3 hand-foot syndrome events were reported. Conclusions: Combination treatment with capecitabine and AI used as a first line or second line treatment was safe with much lowered toxicity. Prospective randomized clinical trials should evaluate the use of combination therapy in advanced breast cancer to confirm these findings.

• Radiation Oncology Journal
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• v.19 no.2
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• pp.171-180
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• 2001

Purpose : Expression of TIMP, intrinsic inhibitor of MMP, is regulated by signal transduction in response to genotoxins and is likely to be an important step in metastasis, angiogenesis and wound healing after ionizing radiation. Therefore, we studied radiation mediated TIMP expression and its mechanism in head and neck cancer cell lines. Materials and Methods : Human head and neck cancer cell lines established at Asan Medical Center were used and radiosensitivity $(D_0)$, radiation cytotoxicity and metastatic potential were measured by clonogenic assay, n assay and invasion assay, respectively. The conditioned medium was prepared at 24 hours and 48 hours after 2 Gy and 10 Gy irradiation and expression of TIMP protein was measured by Elisa assay with specific antibodies against human TIMP. hTIMP1 promoter region was cloned and TIMP1 luciferase reporter vector was constructed. The reporter vector was transfected to AMC-HN-1 and -HN-9 cells with or without expression vector Ras, then the cells were exposed to radiation or PMA, PKC activator. EMSA was peformed with oligonucleotide (-59/-53 element and SP1) of TIMP1 promoter. Results : $D_0$ of HN-1, -2, -3, -5 and -9 cell lines were 1.55 Gy, 1.8 Gy, 1.5 Gt, 1.55 Gy and 2.45 Gy respectively. n assay confirmed cell viability, over $94\%$ at 24hrs, 48hrs after 2 Gy irradiation and over 73% after 10 Gy irradiation. Elisa assay confirmed that cells secreted TIMP1, 2 proteins continuously. After 2 Gy irradiation, TIMP2 secretion was decreased at 24hrs in HN-1 and HN-9 cell lines but after 10 Gy irradiation, it was increased in all cell lines. At 48hrs after irradiation, it was increased in HN-1 but decreased in HN-9 cells. But the change in TIMP secretion by RT was mild. The transcription of TIMP1 gene in HN-1 was induced by PMA but in HN-9 cell lines, it was suppressed. Wild type Ras induced the TIMP-1 transcription by 20 fold and 4 fold in HN-1 and HN-9 respectively. The binding activity to -59/-53, AP1 motif was increased by RT, but not to SP1 motif in both cell lines. Conclusions : We observed the difference of expression and activity of TIMPs between radiosensitive and radioresistant cell line and the different signal transduction pathway between in these cell lines may contribute the different radiosensitivity. Further research to investigate the radiation response and its signal pathway of TIMPs is needed.

• Korean Journal of Pharmacognosy
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• v.35 no.2 s.137
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• pp.110-115
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• 2004

For the evaluation of anti-tumor activity of Korean Oldenlandia Herb (KOH) and Radix (KOR), our experiment was performed with methanol extracts of KOH and KOR. They did not shown any cytotoxicity against HT1080 cell lines. However, they effectively showed anti-metastatic activity through inhibition of the adhesion of HT1080 cells to gelatin, downregulated the expression of MMP2 and uPA and upregulated the expression of TIMP2. They also inhibited tube formation of HUVECs induced by bFGF. However, they did not affect DNA topoisomerase I activity. Simiarly, the T/Cs % in KOH and KOR treated mice were increased 134.9% and 171 %, respectively at 2500 mg/kg. These results suggest that KOH and KOR exert anti-tumor activity via anti-metastatic and anti-angiogenic activities. The further study for isolation of effective compounds and its exact mechanism and comparative study with Chinese Oldenlandia Herba will be required.

• Journal of Life Science
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• v.33 no.2
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• pp.149-157
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• 2023

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that affects not only the survival and growth of cancer cells but also the activity of immune cells. Although it has been generally accepted that cancer cell-derived TGF-β could promote the survival and growth of early cancer cells and have immunosuppressive roles, it has been known that TGF-β has differential effects according to the type or stage of cancer cells. Therefore, it is hard to clearly define its role in cancer progression and immune responses. This study investigated the effects of TGF-β signaling on the expression of five NKG2D ligands and the NK cell-mediated anticancer immune response in the primary colon cancer cell line KM12C and its two metastatic cell lines, KM12SM and KM12L4A. At the surface protein level, exogenous TGF-β decreased the expression of MICA, MICB, ULBP1, and ULBP2, and galunisertib increased the expression of MICA, MIAB, ULBP1, ULBP2, and ULBP3 in KM12C. However, KM12SM and KM12L4A showed no significant changes in the expression of NKG2DLs after treatment with TGF-β or galunisertib. TGF-β signaling inhibition via galunisertib improved the NK cell-mediated anticancer immune response against KM12C but did not show a significant response to KM12SM and KM12L4A. Therefore, the suppression of TGF-β signaling could improve the NK cell-mediated anticancer immune response against KM12C. However, an increase in NKG2DLs expression and an enhanced NK cell-mediated cancer immune response is hard to expect due to the alteration of TGF-β signaling in KM12SM and KM12L4A.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.1197-1200
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• 2015

Breast cancer metastasis is a major cause of cancer-related death in women. However, markers for diagnosis of breast cancer metastasis are rare. Here, we reported that TET1, a tumor suppressor gene, was downregulated and hypermethylated in highly metastatic breast cancer cell lines. Moreover, silencing of TET1 in breast cancer cells increased the migration and spreading of breast cancer cells. In breast cancer clinical samples, TET1 expression was reduced in LN metastases compared with primary tissues. Besides, the methylation level of the TET1 promoter was increased significantly in LN metastases. Taken together, these findings indicate that promoter hypermethylation may contribute to the downregulation of TET1 and could be used as a promising marker for diagnosis in patients with breast cancer metastasis.