• Biomolecules & Therapeutics
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• v.31 no.2
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• pp.210-218
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• 2023

Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin. IL-8 treatment significantly decreased AR and E-cadherin expression. IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gβγ inhibitor. In PC-3 androgen-refractory prostate cancer cells, IL-8 knockdown reduced expressions of CXCR2, MMP-2/9, Snail, and vimentin, and increased AR and E-cadherin expressions at the mRNA and protein levels. Co-culture with MEG-01 human megakaryocytic cells secreting high levels of IL-8 induced gene expression changes in both LNCaP and PC-3 cells, similar to those induced by IL-8 treatment. The altered gene expressions were accompanied by significant activation of transcription factor Snail in LNCaP and PC-3 cells. Treatment with the CXCR blocker navarixin inhibited the invasion of PC-3 cells but not LNCaP cells. However, invasion induced by MEG-01 was inhibited by navarixin in both LNCaP and PC-3 cells. The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.1
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• pp.83-91
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• 2024

Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor activated under hypoxic conditions, and it plays a crucial role in cellular stress regulation. While HIF-1α activity is essential in normal tissues, its presence in the tumor microenvironment represents a significant risk factor as it can induce angiogenesis and confer resistance to anti-cancer drugs, thereby contributing to poor prognoses. Typically, HIF-1α undergoes rapid degradation in normoxic conditions via oxygen-dependent degradation mechanisms. However, certain cancer cells can express HIF-1α even under normoxia. In this study, we observed an inclination toward increased normoxic HIF-1α expression in cancer cell lines exhibiting increased HDAC6 expression, which prompted the hypothesis that HDAC6 may modulate HIF-1α stability in normoxic conditions. To prove this hypothesis, several cancer cells with relatively higher HIF-1α levels under normoxic conditions were treated with ACY-241, a selective HDAC6 inhibitor, and small interfering RNAs for HDAC6 knockdown. Our data revealed a significant reduction in HIF-1α expression upon HDAC6 inhibition. Moreover, the downregulation of HIF-1α under normoxic conditions decreased zinc finger E-box-binding homeobox 1 expression and increased E-cadherin levels in lung cancer H1975 cells, consequently suppressing cell invasion and migration. ACY-241 treatment also demonstrated an inhibitory effect on cell invasion and migration by reducing HIF-1α level. This study confirms that HDAC6 knockdown and ACY-241 treatment effectively decrease HIF-1α expression under normoxia, thereby suppressing the epithelial-mesenchymal transition. These findings highlight the potential of selective HDAC6 inhibition as an innovative therapeutic strategy for lung cancer.

• Annals of Hepato-Biliary-Pancreatic Surgery
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• v.26 no.2
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• pp.138-143
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• 2022

Backgrounds/Aims: Pancreaticoduodenectomy (PD) is a standard surgical procedure for patients with periampullary cancer. During the follow-up period after PD, recurrence can be observed in various places with different prognosis. The aim of this study was to clarify the pattern of recurrence and factors affecting the survival of patients with periampullary cancer. Methods: Overall, 88 patients who received PD for distal common bile duct cancer or ampulla of Vater cancer were finally included and their clinical characteristics were analyzed. Patients were divided into three groups: recurrence-free (RF) group, an isolated locoregional recurrence (LR) group, and a distant metastasis (DM) group. Prognostic factors affecting recurrence in each group were analyzed and a survival analysis was performed. Results: Perineural invasion (PNI), T stage, and lymphovascular invasion (LVI) were significant risk factors for LR and PNI, lymph node metastasis, LVI, and T stage were associated with DM group compared to RF group in univariate analysis, respectively. N stage and PNI were significant risk factors (p = 0.046, p = 0.041) in overall survival of the LR and the DM groups. There was no significant difference in 5-year overall survival between the LR and DM groups. Conclusions: T stage was a significant risk factor of LR, while PNI was a significant risk factor of DM. There was no significant difference in overall survival depending on the site of recurrence.

• Journal of Gastric Cancer
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• v.12 no.2
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• pp.81-87
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• 2012

Purpose: The aim of the present study was to assess the association between the pre-operative plasma fibrinogen level and the adjacent organ involvement in advanced gastric cancer. Materials and Methods: A total of 923 pre-operative plasma samples were obtained from 923 patients diagnosed clinically as having advanced gastric cancer, and fibrinogen levels were measured by immunoassay. Associations between fibrinogen levels and clinicopathologic findings (depth of tumor, adjacent organ involvement, and lymph node metastasis), along with survival were examined by univariate and multivariate analyses. Results: Tumor size, tumor depth, and the presence of lymph node metastasis were found to be positively correlated with the preoperative plasma fibrinogen levels (P<0.001). Fifty (5.4%) patients had adjacent organ involvement. Lymphatic invasion (P<0.001), tumor size (P<0.001), clinical T (depth of invasion) stage (P<0.001), and clinical nodal stage (P=0.018) were found to be associated with adjacent organ involvement. Univariate and multivariate regression analyses showed that a preoperatively elevated plasma fibrinogen level was associated with adjacent organ involvement (P<0.001, 0.028), and Kaplan-Meier analysis showed that it was associated with poorer survival (P<0.001). Conclusions: Plasma fibrinogen was found to be a clinically useful marker of adjacent organ involvement and overall survival. When a high fibrinogen level is encountered, preoperatively, adjacent organ involvement should be suspected in clinically advanced gastric cancer.

• Korean Journal of Head & Neck Oncology
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• v.11 no.2
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• pp.125-131
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• 1995

The authors present 15 cases in which the diagnosis of thyroid cancer was established pathologically among 300 cases of Graves' disease diagnosed clinically at Chosun University Hospital, from January 1982 to December 1994. These cases were analyzed in order to establish guidelines for prophylactic node dissection as part of the initial management of thyroid cancer in patients with Graves' disease. The analysis revealed the following: 1) The average age of the 15 patients was 34.5 years and the male: female ratio was 1 : 4.0. 2) In 8 of the 15 cases(53.5 %) the occult thyroid carcinoma measured less than 1.5cm. 3) The degree of invasivensess manifested in these fifteen cases may be summarized as follows: In Group 1(6 cases) there was absence of microscopic capsular invasion and of lymphnode metastasis. In Group 11(4 cases) threre was microscopic capsular invasion but absence of lymphnode metastasis: In Group III(4 cases) there was either extrathyrodal soft tissue invasion or regional lymph node metastasis: and in Group IV(1 case) there was lymphnode invasion and distant metastasis. 4) Thirteen patients underwent either subtotal or near total thyroidectomy, and 2 patients underwent total thyroidectomy. Seven patients underwent some type of neck dissection, as follows: anterior compartment dissection in one of the cases in Group I; functional neck dissection in two cases and jugular node dissection in one case in Group II; and anterior compartment dissection in one case and modified radical neck dissection in two cases in Group III. 5) The author propose the following guidelines for prophylactic initial node dissection when a unexpected coexisting thyroid carcinoma in encountered on the frozen section during the surgical management of Graves' disease; Group I cases do not require initial neck dissection in group II, anterior compartment dissection in sufficient. In Group III, either jugular node dissection or functional neck dissection should be performed, and followed by postoperative Ra$^{131}$I therapy, Group IV requires Ra$^{131}$I therapy with or without modified radical neck dissection depending in the patient's condition.

• Journal of Life Science
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• v.26 no.5
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• pp.614-619
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• 2016

The prostate-apoptosis-response-gene-4 (Par-4) protein has been identified as an effector of cell death in response to various apoptotic stimuli in prostate cancer cells. We found that overexpression of Par-4 by stable transfection inhibits cell migration and invasion in Caki cells. The expression of various matrix metalloproteinases (MMPs) has been implicated in the invasion and metastasis of cancer cells. In this study, we investigated whether ectopic expression of Par-4 modulates MMP-2 expression and activity in human renal carcinoma Caki cells. We found that overexpression of Par-4 markedly inhibited MMP-2 activity, but not MMP-9 activity. However, loss of the leucine zipper domain of Par-4 (Par-4 ΔLZ#1 and #2) did not inhibit MMP-2 activity. Further, knock-down of Par-4 with the corresponding siRNA resulted in increased invasion and metastasis of renal carcinoma Caki cells. Interestingly, overexpression or knock-down of Par-4 did not affect the expression levels of MMP-2 mRNA. Taken together, our findings suggest that Par-4 may inhibit MMP-2 activity through its post-transcriptional regulation in renal carcinoma Caki cells.

• Korean Journal of Head & Neck Oncology
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• v.12 no.1
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• pp.8-15
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• 1996

When thyroid carcinoma invades the larynx or trachea, the proper treatment is needed because of significant morbidity and mortality due to airway obstruction. Hemoptysis and dyspnea are the result of intraluminal extension of the tumor and call for immediate investigation with endoscopic examination and CT. If the thyroid carcinoma with extracapsular spread invades only outer perichondrium of the tracheal or laryngeal cartilage, the shaving operation would be sufficient, but if the tumor invades the cartilage or if there is intraluminal invasion, it is mandatory to remove partial or total part of some aerodigestive tract structures. We retrospectively analyzed 14 surgical cases of the thyroid cancer with laryngotracheal invasion(12 papillary carcinomas and 2 anaplastic carcinomas) at the Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital. The analysis was focused on clinical manifestation, pathologic findings, types of management and results. Survival result was not adequately analyzed due to some recently operated cases.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.427-432
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• 2014

Isocitrate dehydrogenase (IDH) is of great importance in cell metabolism and energy conversion. IDH mutation in glioma cells is reported to be associated with an increased overall survival. However, effects biological behavior of therapy of gliomas are unclear. Here, we investigated the influence of wild-type and mutated IDH genes on glioma cell biological behavior and response to chemotherapy. Relevant mechanisms were further explored. We designed our study on the background of the IDHR132H mutation. Stable cell lines were constructed by transfection. The CCK-8 method was used to assess cell proliferation, flow cytometry for the cell cycle and cell apoptosis, and the transwell method for cell invasion. Nude mouse models were employed to determine tumorigenesis and sensitivity to chemotherapy. Western blotting was used to detect relevant protein expression levels. We found that overexpression of wild IDH1 gene did not cause changes in the cell cycle, apoptosis and invasion ability. However, it resulted in chemotherapy resistance to a high dose of temozolomide (TMZ) in vivo and in vitro. The IDH1 mutation caused cell cycle arrest in G1 stage and a reduction of proliferation and invasion ability, while raising sensitivity to chemotherapy. This may provide an explanation for the better prognosis of IDH1 mutated glioma patients and the relative worse prognosis of their wild-type IDH1 counterparts. We also expect IDH1 mutations may be optimized as new targets to improve the prognosis of glioma patients.

• The Journal of Internal Korean Medicine
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• v.37 no.1
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• pp.16-25
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• 2016

Objectives: Gilgyung-tang (GGT) has been used as one of the main multi-herb formulas to treat “Peo-ong” (lung abscess). In this study, we investigated the inhibitory effects of water extracts of GGT on cell migration and invasion, two critical cellular processes that are often deregulated during metastasis, in human bladder cancer 5637 cells.Methods: Effects on cell viability were quantified using an MTT assay. To analyze the anti-metastatic effects, we conducted a wound healing migration assay, an in vitro invasiveness assay, and a measurement of the transepithelial electrical resistance (TER). The expression of protein and mRNA were measured by Western blotting and real-time polymerase chain reaction (RT-PCR), respectively.Results: GGT markedly inhibited the cell motility and invasiveness of 5637 cells within the concentration range that was not cytotoxic. The inhibitory effects of GGT on cell invasiveness were associated with tightening of the tight junctions (TJs), which was demonstrated by an increase in the TER. The RT-PCR and Western blotting results indicated that GGT decreased the levels of claudin proteins. GGT also inhibited the activity and expression of matrix metalloproteinase (MMP)-2 and -9 and simultaneously increased the levels of tissue inhibitor of metalloproteinase-1 and -2.Conclusions: Our findings suggest that GGT reduces both the migration and the invasion of 5637 cells by modulating the activity of TJs and MMPs.

• Radiation Oncology Journal
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• v.11 no.2
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• pp.347-354
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• 1993

This is a retrospective analysis of 67 patients with histologically proven invasive carcinoma of uterine cervix treated with surgery followed by adjuvant radiotherapy at Inje University Seoul Paik Hospital between october 1983 and september 1991, Postoperative radiotherapy was carried out in patients with high risks of locoregional recurrence such as positive pelvic lymph node (38 pts), large tumor size more than 3 cm (22 pts), cervical stromal invasion more than 2/3 (46 pts), parametrial involvement (9 pts), positive resection margin (14 pts), endo/myometrial extension (10 pts), and angiolymphatic invasion (13 pts). Stage I A, I B, and IIA were 2 $(3\%),$ 39 $(58.2\%),\;and\;26\;(38.8\%),$ respectively. Median follow-up period was 48 months with ranges from 13 to 115 months. All 67 patients were treated externally with standard pelvic field with radiation dose ranging from 4080 to 6120 cGy in 4~6 weeks period of time. Of these, 45 patients received intracavitary radiotherapy. The overall survival rate and disease free survival rate at 5-year were $88.0\%\;and\;82.1\%,$ respectively. The survival rates by stage were $87.1\%$ in IB and $88.4\%$ in IIA. Local control rate was $80.6\%(58\;pts).$ The treatment failure was noted in 12 of 67 patients $(17.9\%):$ locoregional failure in $7(10.4\%),$ distant metastasis in 3 $(4.5\%),$ and locoregional and distant metastasis in $2(3\%),$ The univariate analysis of prognostic factors disclosed endo/myometrial extension as a significant factor of survival and recurrence $(70.0\%\;vs\;91.1\%\;P<0.05\;&\;30.0\%\;vs\;15.8\%,\;respectively).$ The complication of postoperative radiothrapy was not significant and all patient were well tolerated. In conclusion, postoperative radiotherapy in patients with high risks of locoreginal recurrence is relatively well tolerated and it gives significantly improved survival rate especially in patients with positive lymph nodes, bulky tumor size $(\geqq3\;cm),$ parametrial involvement, cervical stromal invasion more than 2/3, positive resection margin and angiolymphatic invasion.