• Korean Journal of Pharmacognosy
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• v.49 no.4
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• pp.285-290
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• 2018

Harmine, a beta-carboline alkaloid isolated from the seeds of Peganum harmala has been reported as a promising drug candidate for cancer therapy. However, the effect of harmine on breast cancer remains still unclear. In this study, the effect of harmine on the cell proliferation, migration, and invasion of breast cancer MDA-MB231 cells and the underlying mechanism were investigated. The results indicated that harmine inhibited the proliferation MDA-MB231 cells in a dose-dependent manner and markedly suppressed migration and invasion of MDA-MB231 cells. The mechanism involved in part through Notch signaling. The Notch activity was significantly inhibited by harmine treatment and harmine suppressed the expression of Jagged1 which is a key ligand to activate Notch signaling. These findings suggest a novel mechanism of harmine on anti-cancer activity and harmine may act as a potential therapeutic drug for breast cancer treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4815-4822
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• 2012

Invasion and metastasis are the major causes of cancer-related death. Pharmacological or therapeutic interventions such as chemoprevention of the progression stages of neoplastic development could result in substantial reduction in the incidence of cancer mortality. (-)-Epigallocatechin-3-gallate (EGCG), a promising chemopreventive agent, has attracted extensive interest for cancer therapy utilizing its antioxidant, anti-proliferative and inhibitory effects on angiogenesis and tumor cell invasion. In this study, we assessed the influence of EGCG on the proliferative potential of HeLa cells by cell viability assay and authenticated the results by nuclear morphological examination, DNA laddering assay and cell cycle analysis. Further we analyzed the anti-invasive properties of EGCG by wound migration assay and gene expression of MMP-9 and TIMP-1 in HeLa cells. Our results indicated that EGCG induced growth inhibition of HeLa cells in a dose- and time-dependent manner. It was observed that cell death mediated by EGCG was through apoptosis. Interestingly, EGCG effectively inhibited invasion and migration of HeLa cells and modulated the expression of related genes (MMP-9 and TIMP-1). These results indicate that EGCG may effectively suppress promotion and progression stages of cervical cancer development.

• Journal of Gastric Cancer
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• v.12 no.3
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• pp.149-155
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• 2012

Purpose: Although serosal invasion is a critical predisposing factor for peritoneal dissemination in advanced gastric cancer, the accuracy of preoperative assessment using routine imaging studies is unsatisfactory. This study was conducted to identify high-risk group for serosal invasion using preoperative factors in patients with advanced gastric cancer. Materials and Methods: We retrospectively analyzed clinicopathological features of 3,529 advanced gastric cancer patients with Borrmann type I/II/III who underwent gastrectomy at Korea Cancer Center Hospital between 1991 and 2005. We stratified patients into low-(${\leq}40%$), intermediate-(40~70%), and high-risk (>70%) groups, according to the probability of serosal invasion. Results: Borrmann type, size, longitudinal and circumferential location, and histology of tumors were independent risk factors for serosal invasion. Most tumors of whole stomach location or encircling type had serosal invasion, so they belonged to high-risk group. Patients were subdivided into 12 subgroups in combination of Borrmann type, size, and histology. A subgroup with Borrmann type II, large size (${\geq}7$ cm), and undifferentiated histology and 2 subgroups with Borrmann type III, large size, and regardless of histology belonged to high-risk group and corresponded to 25% of eligible patients. Conclusions: This study have documented high-risk group for serosal invasion using preoperative predictors. And risk stratification for serosal invasion through the combination with imaging studies may collaboratively improve the accuracy of preoperative assessment, reduce the number of eligible patients for further staging laparoscopy, and optimize therapeutic strategy for each individual patient prior to surgery.

• Journal of Gastric Cancer
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• v.5 no.2
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• pp.113-119
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• 2005

Purpose: Some controversies exist over the prognostic values of lymphatic, venous, and neural invasion in patients with gastric cancer. This study was conducted to confirm the prognostic values of these histopathologic factors in gastric cancer patients who received a gastrectomy. Materials and Methods: Data for clinicopathologic factors and clinical outcomes were collected retrospectively from the medical records of 1,018 gastric cancer patients who received a gastrectomy at Yeungnam University Medical Center between January 1995 and December 1999. A statistical analysis was done using the SPSS program for Windows (Version 10.0, SPSS Inc., USA). The Kaplan-Meier method was used for the survival analysis. Prognostic factors were analyzed by using a multivariate analysis with Cox proportional hazard regression model. Results: Ages ranged from 21 to 79 (median age, 56). A univariate analysis revealed that age, tumor size, location, gross type, depth of invasion, extent of gastrectomy or lymph node dissection, lymph node metastasis, distant metastasis, lymphatic invasion, venous invasion, neural invasion, pathologic stage, histologic type, and curability of surgery had statistical significance. Among these factors, lymph node metastasis, curability of surgery, neural invasion, lymphatic invasion, and depth of invasion were found to be independent prognostic factors by using a multivariate analysis. Venous invasion showed no prognostic value in the multivariate analysis. Conclusion: Neural invasion and lymphatic invasion are useful parameters in determining a prognosis for gastric cancer patients.

• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.286-292
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• 2012

All-trans retinoic acid (ATRA) is currently used in adjuvant differentiation-based treatment of residual or relapsed neuroblastoma (NB). It has been reported that short-term ATRA treatment induces migration and invasion of SH-SY5Y via transglutaminase-2 (Tgase-2). However, the detailed mechanism of Tgase-2's involvement in NB cell invasion remains unclear. Therefore we investigated the role of Tgase-2 in invasion of NB cells using SH-SY5Y cells. ATRA dose-dependently induced the invasion of SH-SY5Y cells. Cystamine (CTM), a well known tgase inhibitor suppressed the ATRA-induced invasion of SH-SY5Y cells in a dose-dependent manner. Matrix metalloproteinase -9 (MMP-9) and MMP-2, well known genes involved in invasion of cancer cells were induced in the ATRA-induced invasion of the SH-SH5Y cells. Treatment of CTM suppressed the MMP-9 and MMP-2 enzyme activities in the ATRA-induced invasion of the SH-SY5Y cells. To confirm the involvement of Tgase-2, gene silencing of Tgase-2 was performed in the ATRA-induced invasion of the SH-SH5Y cells. The siRNA of Tgase-2 suppressed the MMP-9 and MMP-2 activity of the SH-SY5Y cells. MMP-2 and MMP-9 are well known target genes of NF-${\kappa}B$. Therefore the relationship of Tgase-2 and NF-${\kappa}B$ in the ATRA-induced invasion of the SH-SY5Y cells was examined using siRNA and CTM. ATRA induced the activation of NF-${\kappa}B$ in the SH-SY5Y cells and CTM suppressed the activation of NF-${\kappa}B$. Gene silencing of Tgase-2 suppressed the MMP expression by ATRA. These results suggested that Tgase-2 might be a new target for controlling the ATRA-induced invasion of NBs.

• Nutrition Research and Practice
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• v.3 no.4
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• pp.259-264
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• 2009

We examined the inhibitory effects of loquat methanol extract on the adhesion, migration, invasion and matrix metalloproteinase (MMP) activities of MDA-MB-231 human breast cancer cell line. Cells were cultured with DMSO or with 10, 25, or 50 ${\mu}g/ml$ of loquat methanol extract. Both leaf and seed extracts significantly inhibited growth of MDA-MB-231 cells in a dose-dependent manner, although leaf extract was more effective. Adhesion and migration were significantly inhibited by loquat extracts in a dose-dependent manner. Loquat extract also inhibited the invasion of breast cancer cells in a dose-dependent manner and leaf extract was more effective than seed extract. MMP-2 and MMP-9 activities were also inhibited by loquat extract. Our results indicate that methanol extracts of loquat inhibit the adhesion, migration and invasion of human breast cancer cells partially through the inhibition of MMP activity and leaf extract has more anti-metastatic effects in cell based assay than seed extract. Clinical application of loquat extract as a potent chemopreventive agent may be helpful in limiting breast cancer invasion and metastasis.

• Journal of Gastric Cancer
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• v.14 no.4
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• pp.252-258
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• 2014

Purpose: The macroscopic diagnosis of tumor invasion through the serosa during surgery is not always distinct in patients with gastric cancer. The prognostic impact of the difference between macroscopic findings and pathological diagnosis of serosal invasion is not fully elucidated and needs to be re-evaluated. Materials and Methods: A total of 370 patients with locally advanced pT2 to pT4a gastric cancer who underwent curative surgery were enrolled in this study. Among them, 155 patients with pT3 were divided into three groups according to the intraoperative macroscopic diagnosis of serosal invasion, as follows: serosa exposure (SE)(-) (no invasion, 72 patients), SE(${\pm}$) (ambiguous, 47 patients), and SE(+) (definite invasion, 36 patients), and the clinicopathological features, surgical outcomes, and disease-free survival (DFS) were analyzed. Results: A comparison of the 5-year DFS between pT3_SE(-) and pT2 groups and between pT3_SE(+) and pT4a groups revealed that the differences were not statistically significant. In addition, in a subgroup analysis of pT3 patients, the 5-year DFS was 75.1% in SE(-), 68.5% in SE(${\pm}$), and 39.4% in SE(+) patients (P<0.05). In a multivariate analysis to evaluate risk factors for tumor recurrence, macroscopic diagnosis (hazard ratio [HR], SE(-) : SE(${\pm}$) : SE(+)=1 : 1.01 : 2.45, P=0.019) and lymph node metastasis (HR, N0 : N1 : N2 : N3=1 : 1.45 : 2.20 : 9.82, P<0.001) were independent risk factors for recurrence. Conclusions: Gross inspection of serosal invasion by the surgeon had a strong impact on tumor recurrence in gastric cancer patients. Consequently, the gross appearance of serosal invasion should be considered as a factor for predicting patients' prognosis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10513-10524
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• 2015

Background: Metastasis is a major reason for poor prognosis in patients with cancer, including hepatocellular carcinoma (HCC). A salient feature is the ability of cancer cells to colonize different organs. Long non-coding RNAs (lncRNAs) play important roles in numerous cellular processes, including metastasis. Materials and Methods: In this study, the lncRNA expression profiles of two HCC cell lines, one with high potential for metastasis to the lung (HCCLM3) and the other to lymph nodes (HCCLYM-H2) were assessed using the Arraystar Human LncRNA Array v2.0, which contains 33,045 lncRNAs and 30,215 mRNAs. Coding-non-coding gene co-expression (CNC) networks were constructed and gene set enrichment analysis (GSEA) was performed to identify lncRNAs with potential functions in organ-specific metastasis. Levels of two representative lncRNAs and one representative mRNA, RP5-1014O16.1, lincRNA-TSPAN8 and TSPAN8, were further detected in HCC cell lines with differing metastasis potential by qRT-PCR. Results: Using microarray data, we identified 1,482 lncRNAs and 1,629 mRNAs that were differentially expressed (${\geq}1.5$ fold-change) between the two HCC cell lines. The most upregulated lncRNAs in H2 were RP11-672F9.1, RP5-1014O16.1, and RP11-501G6.1, while the most downregulated ones were lincRNA-TSPAN8, lincRNA-CALCA, C14orf132, NCRNA00173, and CR613944. The most upregulated mRNAs in H2 were C15orf48, PSG2, and PSG8, while the most downregulated ones were CALCB, CD81, CD24, TSPAN8, and SOST. Among them, lincRNA-TSPAN8 and TSPAN8 were found highly expressed in high lung metastatic potential HCC cells, while lowly expressed in no or low lung metastatic potential HCC cells. RP5-1014O16.1 was highly expressed in high lymphatic metastatic potential HCC cell lines, while lowly expressed in no lymphatic metastatic potential HCC cell lines. Conclusions: We provide the first detailed description of lncRNA expression profiles related to organ-specific metastasis in HCC. We demonstrated that a large number of lncRNAs may play important roles in driving HCC cells to metastasize to different sites; these lncRNAs may provide novel molecular biomarkers and offer a new basis for combating metastasis in HCC cases.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.13
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• pp.5331-5335
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• 2015

Purpose: The aim of this study was to compare the tumor-free and overall survival rates between patients with low-risk endometrial cancer who underwent surgical staging and those who did not undergo surgical staging. Materials and Methods: Data, including demographic characteristics, grade of the tumor, myometrial invasion, cervical involvement, peritoneal washing, lymph node involvement, lymphovascular space invasion, postoperative complication, adjuvant treatment, cancer recurrence, and tumor-free and overall survival rates, for patients with low-risk endometrioid endometrial cancer who were treated surgically with and without pelvic and paraaortic lymph node dissection (LND) were analyzed retrospectively. The patients diagnosed with endometrioid endometrial cancer including the following criteria were considered low-risk: 1) a grade 1 (G1) or grade 2 (G2) endometrioid histology; 2) myometrial invasion of <50% upon magnetic resonance imaging (MRI); 3) no stromal glandular or stromal invasion upon MRI; and 4) no evidence of intra-abdominal metastasis. Then the patients at low-risk were divided into two groups; group 1 (n=117): patients treated surgically with pelvic and paraaortic LND and group 2 (n=170): patients treated surgically without pelvic and paraaortic LND. Results: There was no statistical significance when the groups were compared in terms of lymphovascular space invasion, cervical involvement, positive cytology, and recurrence, whereas the administration of an adjuvant therapy was higher in group 2 (p<0.005). The number of patients with positive pelvic nodes and the number of metastatic pelvic nodes were significantly higher in the group with positive LVI than in the group without LVI (p<0.005). No statistically significant differences were detected between the groups in terms of tumor-free survival (p=0.981) and overall survival (p=0.166). Conclusions: Total hysterectomy with bilateral salpingo-oophorectomy and stage-adapted postoperative adjuvant therapy without pelvic and/or paraaortic lymphadenectomy may be safe and efficient treatments for low-risk endometrial cancer.

• Journal of Cancer Prevention
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• v.21 no.2
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• pp.88-94
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• 2016

Background: Breast cancer is the most common malignant disease in women. The patients with advanced breast cancer develop metastasis to bone. Bone metastasis and skeletal-related events by breast cancer are frequently associated with the invasiveness of breast cancer cells and osteoclasts-mediated bone resorption. Forsythia koreana is used in oriental traditional medicine to treat asthma, atopy, and allergic diseases. The aim of this study was to evaluate the inhibitory effects of F. koreana extracts on the invasion of breast cancer cells and bone resorption by osteoclasts. Methods: Cell viability was measured by an MTT assay and the migration and invasion of MDA-MB-231 cells were detected by a Boyden chamber assay. The formation of osteoclasts and pit was detected using tartrate-resistant acid phosphatase staining and calcium phosphate-coated plates, respectively. The activities of matrix metalloproteinases (MMPs) and cathepsin K were evaluated by gelatin zymography and a cathepsin K detection kit. Results: The fruit and leaf extracts of F. koreana significantly inhibited the invasion of MDA-MB-231 cells at noncytotoxic concentrations. The fruit extract of F. koreana reduced the transforming growth factor ${\beta}1-induced$ migration, invasion and MMPs activities of MDA-MB-231 cells. In addition, the fruit, branch, and leaf extracts of F. koreana also inhibited the receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation and osteoclast-mediated bone-resorbing activity by reducing the activities of MMPs and cathepsin K. Conclusions: The extracts of F. koreana may possess the potential to inhibit the breast cancer-induced bone destruction through blocking invasion of breast cancer cells, osteoclastogenesis, and the activity of mature osteoclasts.