• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.4019-4023
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• 2014

Metformin has been shown to be useful in reducing insulin resistance by restoring sensitivity. Recent evidence suggests that metformin might also possess anti-tumour activity. This study aimed to investigate the effects of cisplatin combined with metformin on the proliferation, invasion and migration of HNE1/DDP human nasopharyngeal carcinoma (NPC) cells, and to provide a new target for treating metastasis. The MTT assay was used to assess viability of HNE1/DDP cells after exposure to different concentrations of 2, 5-diaminopyrimidine-4, 6-diol (DDP; 2, 4, 8, 16, and $32{\mu}mol{\cdot}L^{-1}$), metformin (5, 10, 15, 20, and $25{\mu}mol{\cdot}L^{-1}$), and $4{\mu}mol{\cdot}L^{-1}$ of DDP combined with metformin. Wound healing and transwell migration assays were performed to assess cell migration and invasion, and expression of E-cadherin and MMP-9 was detected using Western blotting. MTT assay results showed that DDP could inhibit the proliferation of HNE1/DDP cells in a time- and concentration-dependent manner, with an IC50 of $32.0{\mu}mol{\cdot}L^{-1}$ at 24 h (P < 0.05), whereas low concentrations of DDP had almost no inhibitory effects on cell invasion and migration. DDP combined with metformin significantly inhibited cell invasion and migration. In addition, genes related to migration and invasion, such as those of E-cadherin and MMP-9, showed differential expression in the NPC cell line HNE1/DDP. In the present study, with an increasing concentration of metformin, the expression of MMP-9 was downregulated whereas that of E-cadherin was significantly upregulated. Taken together, our results show that cisplatin combined with metformin has effects on proliferation, invasion, and migration of human NPC cells.

• Tuberculosis and Respiratory Diseases
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• v.49 no.2
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• pp.189-197
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• 2000

Background : Tissue inhibitor of metalloproteinase is a natural inhibitor that counteracts pro teolytic enzymes essential to the invasion of cancer cell. Whether or not TIMP-2 gene transfer via adenovirus could inhibit the invasion of lung cancer cell iη vitro was evaluated for the future purpose of gene therapy against lung cancer. Methods : Recombinant adenovirus-TIMP-2(Ad-TIMP-2) was generated by homologous recombination after pACCMV-TIMP-2 and pJM17 were cotransfected into 293 cell by standard calcium phosphate coprecipitate method. Calu-6, one of the most invasive lung cancer cells, was transduced with Ad-TIMP-2 or Ad-$\beta$gal. Anchorage-independent growth and invasiveness were assessed by soft agar clonogenicity assay and invasion assay using two-chamber, well divided by matrigel. Results : Ad-TIMP-2 transduced calu-6 cells produced biologically active TIMP-2 more than 50 times more than parental calu-6. TIMP-2 gene transfer did not suppress the in vitro tumorigenicity. However, two chamber well assay revealed that Ad-TIMP-2 transduction reduced the invasiveness of calu-6 efficiently (12% compared with parental cell) even at low 10moi. Conclusion : Even though TIMP-2 gene transfer did not inhibit in vitro tumorigenicity, it did inhibit invasion of lung cancer cell in vitro. The inhibition of invasion by Ad-TIMP-2 may be a useful strategy for the treatment of lung cancer.

• Journal of Gastric Cancer
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• v.20 no.1
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• pp.1-18
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• 2020

Splenic hilar lymph node dissection has been the standard treatment for advanced proximal gastric cancer. Splenectomy is typically performed as part of this procedure. However, splenectomy has some disadvantages, such as increased risk of postoperative complications, especially pancreatic fistula. Moreover, patients who underwent splenectomy are vulnerable to potentially fatal infection caused by encapsulated bacteria. Furthermore, several studies have shown an association of splenectomy with cancer development and increased risk of thromboembolic events. Therefore, splenectomy should be avoided if it does not confer a distinct oncological advantage. Most studies that compared patients who underwent splenectomy and those who did not failed to demonstrate the efficacy of splenectomy. Based on the results of a randomized controlled trial conducted in Japan, prophylactic dissection with splenectomy is no longer recommended in patients with gastric cancer with no invasion of the greater curvature. However, patients with greater curvature invasion or those with remnant gastric cancer still need to undergo splenectomy to facilitate splenic hilar node dissection. Spleen-preserving splenic hilar node dissection is a new procedure that may help delink splenic hilar node dissection and splenectomy. In this review, we examine the evidence pertaining to the efficacy and disadvantages of splenectomy. We discuss the possibility of spleen-preserving surgery for prophylactic splenic hilar node dissection to overcome the disadvantages of splenectomy.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5133-5139
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• 2013

Background: Perineural invasion (PNI) has been reported as one of the sources of locoregional recurrence in resected pancreatic cancer (PC). However the impact of PNI in resected pancreatic cancer remains controversial. The purpose of this study was to determine the association between PNI status and clinical outcomes. Methods: Publications were identified which assessed prognostic significance of PNI status in resected pancreatic cancer up to February 2013. A meta-analysis was performed to clarify the association between PNI status and clinical outcomes. Results: A total of 21 studies met the inclusion criteria, covering 4,459 cases. Analysis of these data showed that intrapancreatic PNI was correlated with reduced overall survival only in resected pancreatic ductal adenocarcinoma (PDAC) patients (HR=1.982, 95%CI: 1.526-2.574, p=0.000). Extrapancreatic PNI was correlated with reduced overall survival in all resected pancreatic cancer patients (HR=1.748, 95%CI: 1.372-2.228, p=0.000). Moreover, intrapancreatic PNI status may be associated with tumor recurrence in all resected pancreatic cancer patients (HR=2.714, 95%CI: 1.885-3.906, p=0.000). Conclusion: PNI was an independent and poor prognostic factor in resected PDAC patients. Moreover, intrapancreatic PNI status may be associated with tumor recurrence.

• Biomolecules & Therapeutics
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• v.28 no.4
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• pp.370-379
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• 2020

Econazole, a potent broad-spectrum antifungal agent and a Ca²⁺ channel antagonist, induces cytotoxicity in leukemia cells and is used for the treatment of skin infections. However, little is known about its cytotoxic effects on solid tumor cells. Here, we investigated the molecular mechanism underlying econazole-induced toxicity in vitro and evaluated its regulatory effect on the metastasis of gastric cancer cells. Using the gastric cancer cell lines AGS and SNU1 expressing wild-type p53 we demonstrated that econazole could significantly reduce cell viability and colony-forming (tumorigenesis) ability. Econazole induced G0/G1 phase arrest, promoted apoptosis, and effectively blocked proliferation- and survival-related signal transduction pathways in gastric cancer cells. In addition, econazole inhibited the secretion of matrix metalloproteinase- 2 (MMP-2) and MMP-9, which degrade the extracellular matrix and basement membrane. Econazole also effectively inhibited the metastasis of gastric cancer cells, as confirmed from cell invasion and wound healing assays. The protein level of p53 was significantly elevated after econazole treatment of AGS and SNU1 cells. However, apoptosis was blocked in econazole-treated cells exposed to a p53-specific small-interfering RNA to eliminate p53 expression. These results provide evidence that econazole could be repurposed to induce gastric cancer cell death and inhibit cancer invasion.

• Journal of Gastric Cancer
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• v.1 no.2
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• pp.113-118
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• 2001

Purpose: The common features of brain metastases from gastric cancer are unknown because brain metastasis is an uncommon pattern of metastasis. The purpose of this study was to investigate the clinical features of and the prognosis for patients with brain metastases after a curative resection for gastric cancer. Materials and Methods: Twenty-one (21) cases of patients with brain metastases of gastric cancer, who had been treated at the Department of Surgery, Yonsei University College of Medicine, were assessed retrospectively. Results: The mean age was $55.8\pm9.6$ years (range: $34\~70$ years), and the male-to-female ratio was 2.5 : .1. The most common neurologic symptom was headache ($38.5\%$), and no patient was free from the neurologic symptoms. The incidence of parenchymal metastasis (PM: $76.2\%$) was higher than that of leptomeningeal metastasis (LM: $19.0\%$). Patients with gastric cancer and brain metastasis showed high rates of blood and lymphatic vessel invasion (lymphatic vessel invasion: $85.7\%$; blood vessel invasion: $80.9\%$). According to Lauren's classification, the incidence of intestinal types was 14/21 ($66.7\%$), that of diffuse types was 3/21 ($14.3\%$) and that of mixed types was 4/21 ($19.0\%$). The mean interval between the gastrectomy and the diagnosis of brain metastasis was $24.7\pm4.0$ months (PM: 26.8 months; LM: 20.3 months). The median period of survival after diagnosis of brain metastasis was 2 months for paren chymal metastasis and 0 months for leptomeningeal metastasis. Conclusion:.. During a follow-up period, patients with neurologic symptoms should be suspected of having brain metastasis. Early diagnosis and treatment is the only hope to prolong survival in such patients.

• YAKHAK HOEJI
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• v.48 no.3
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• pp.189-196
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• 2004

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) playa key role in tumor invasion and metastasis. As an inhibitor of MMP-2, TIMP-2 is known to block both the invasive and metastatic behavior of cancer cells, and decrease tumor growth activity. We performed this study to investigate the effects of TIMP-2 over-expression induced by retroviral mediated gene transfer in vitro and in vivo. The human colon cancer cell line SW480 was transfected with the retroviral vector encoding TIMP-2. The effects of TIMP-2 over-expression were analyzed by invasion assay and gelatinase activity test in colon cancer cells and tumorigencity in nude mice. In evaluation of the transfection efficiency of the retroviral vector encoding TIMP-2 in colon cancer cells, we confirmed up-regulation of TIMP-2 expression dependent on the time of cell culture. In addition, inhibition of MMP-2 expression in SW480/TIMP-2 was shown by gelatin zymography. In the in vitro invasion assay SW480/TIMP-2 inhibited the invasiveness on matrigel coated with collagen. To determine whether TIMP-2 can modulate in vivo tumorigenicity and metastasis, SW480/TIMP-2 cells were injected subcutaneously in nude mice. The tumor mass formation of SW480/TIMP-2 cells in nude mice was markedly decreased compared to nontransfected cancer cells. These results showed that colon cancer cells transfected with the retroviral vector encoding TIMP-2 inhibits the invasiveness in vitro and tumorigenicity in vivo.

• Journal of Gastric Cancer
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• v.1 no.4
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• pp.197-201
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• 2001

Purpose: There are variants of gastric cancer assoclated with predominantly peritoneal spread of with haematogenous metastases. Perioperative intraperitoneal chemotherapy as an adjuvant to surgery is considered as a rational therapeutic modality to prevent peritoneal spread. We evaluated the influence of early postoperative intraperitoneal chemotherapy on the prognosis of resectable advanced gastric cancer. Materials and Methods: From 1990 to 1995, 246 patients with biopsy proven advanced gastric cancer were enrolled in the study. Among them 123 patients received early postoperative intraperitoneal mitomycin C and 5-fluorouracil. The survival rate was calculated using by the Kaplan-Meier method and was compared using the log-rank test according to 13 clinico-pathologic factors. Multivariate analysis was performed with the Coxproportional hazards model. Results: Gastric resection plusearly postoperative intraperitoneal chemotherapy showed an improved survival rate as compared to surgery alone ($54.1\%\;versus\;40.3\%;$ P=0.0325). Depth of tumor invasion, degree of regional lymph vode metastasis, distant metastasis, tumor size, tumor location, extent of gastric resection, and curability of surgery significantly influenced survival. When a multivariate analysis was performed, depth of tumor invasion, lymph node metastasis, early postoperative intraperitoneal chemotherapy, curability of surgery, and extent of gastric resection emerged as the statistically significant and independent prognostic factors. Conlusion: Early postoperative intraperitoneal chemotherapy is one of the independent prognostic indicators of resectable advanced gastric cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2453-2458
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• 2015

Background: X-linked inhibitor of apoptosis protein (XIAP) associated factor 1 (XAF1) exhibits aberrantly low or absent expression in various human malignancies, closely associated with anti-apoptosis and overgrowth of cancer cells. However, limited attention has been directed towards the contribution of XAF1 to invasion, apoptosis, and cisplatin (DDP)-resistance of epithelial ovarian cancer (EOC) cells. This study aimed to evaluate the potential effects of XAF1 on invasion, cell cycle, apoptosis, and cisplatin-resistance by overexpressing XAF1 in SKOV-3 and SKOV-3/DDP cells. Methods and Results: The pEGFP-C1-XAF1 plasmid was transfected into SKOV-3 and SKOV-3/DDP cells, and the expression of XAF1 at both mRNA and protein levels was analyzed by reverse transcription-PCR and Western blotting. Overexpression of XAF1 suppressed XIAP expression in both SKOV-3 and SKOV-3/DDP cells. Transwell invasion assays demonstrated that XAF1 exerted a strong anti-invasive effect in XAF1-overexpressing cells. Moreover, flow cytometry analysis revealed that XAF1 overexpression arrested the cell cycle at G0/G1 phase, and cell apoptosis analysis showed that overexpression of XAF1 enhanced apoptosis of SKOV-3 and SKOV-3/DDP cells apparently by activating caspase-9 and caspase-3. Furthermore, MTT assay confirmed a dose-dependent inhibitory effect of cisplatin in the tested tumor cells, and overexpression of XAF1 increased the sensitivity of SKOV-3 and SKOV-3/DDP cells to cisplatin-mediated antiproliferative effects. Conclusions: In summary, our data indicated that overexpression of XAF1 could suppress XIAP expression, inhibit invasion, arrest cell cycle, promote apoptosis, and confer cisplatin-sensitivity in SKOV-3 and SKOV-3/DDP cells. Therefore, XAF1 may be further assessed as a potential target for the treatment of both cisplatin-resistant and non-resistant EOCs.

• Journal of Nutrition and Health
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• v.41 no.1
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• pp.13-21
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• 2008

To determine whether indol-3-carbinol (BC, $C_9H_9NO$), an autolysis product of a glucosinolate and a glucobrassicin in vegetables, regulated tight junction proteins (TJ) and suppressed cell invasion in colon cancer cells, this experiment was performed. Our results indicate that I3C inhibit cell growth of HT-29 cells in a dose (0, 50, $100{\mu}M$) and time (0, 24 and 48h) dependent manner. Using the wound healing and matrigel invasion study, respectively, BC inhibits the cell motility and invasion of the ovarian cancer cell line. The TEER values were increased in HT-29 cells grown in transwells treated with BC, reversely, paracellular permeability was decreased in those of condition. Claudin-1, claudin-5, ZO-1 and occuldin have been shown to be positively expressed in HT-29 coloncancer cells. I3C occurs concurrently with a significant decrease in the levels of those of proteins in HT-29 cells. But E-cadherin level in the HT-29 was increased by I3C. The reduction of claudin-1 and claudin-5 protein levels occurred post-transcriptionaly since their mRNA levels are no difference by I3C. Therefore, our results suggest that I3C may be expected to inhibit cancer metastasis and invasion by tighten the cell junction and restoring tight junction in colon cancer cell line, HT-29.