• Molecules and Cells
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• v.42 no.8
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• pp.604-616
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• 2019

Phosphoserine phosphatase (PSPH) is one of the key enzymes of the L-serine synthesis pathway. PSPH is reported to affect the progression and survival of several cancers in an L-serine synthesis-independent manner, but the mechanism remains elusive. We demonstrate that PSPH promotes lung cancer progression through a noncanonical L-serine-independent pathway. PSPH was significantly associated with the prognosis of lung cancer patients and regulated the invasion and colony formation of lung cancer cells. Interestingly, L-serine had no effect on the altered invasion and colony formation by PSPH. Upon measuring the phosphatase activity of PSPH on a serine-phosphorylated peptide, we found that PSPH dephosphorylated phospho-serine in peptide sequences. To identify the target proteins of PSPH, we analyzed the protein phosphorylation profile and the PSPH-interacting protein profile using proteomic analyses and found one putative target protein, IRS-1. Immunoprecipitation and immunoblot assays validated a specific interaction between PSPH and IRS-1 and the dephosphorylation of phospho-IRS-1 by PSPH in lung cancer cells. We suggest that the specific interaction and dephosphorylation activity of PSPH have novel therapeutic potential for lung cancer treatment, while the metabolic activity of PSPH, as a therapeutic target, is controversial.

• Journal of Gastric Cancer
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• v.1 no.3
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• pp.180-186
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• 2001

Purpose: The prognosis for early gastric cancer (EGC) is favorable, and the 10-year disease-specific survival rate is reported to be around $90\%$. The absolute number of recurred EGC is too small to assess the risk factors, so recruitment of a large number of cases for statistical analysis is very difficult. We carried out this study to analyze the incidence and the patterns of recurrence of EGC and to identify the clinicopathological risk factors for recurrence of EGC. Materials and Methods: The authors retrospectively investigated the follow-up records of 1418 patients who underwent a curative resection for EGC from Jan. 1984 to Dec. 1999 at the Korea Cancer Center Hospital and analyzed them with special reference to cancer recurrence. Results: In this retrospective study of 1418 cases, 43 patients died of a recurrence of gastric cancer, and 105 patients died of unrelated causes. The five-year and the ten-year overall survival rates were $89.6\%$ and $81.7\%$, respectively, while the five-year and the ten-year diseasespecific survival rates were $96.5\%$ and $94.3\%$, respectively. The recurrence patterns of the 45 recurred EGC were hematogenous metastasis (19 cases), lymph node (L/N) metastasis (8 cases), locoregional recurrence (2 cases), peritoneal seeding (3 cases), and combined form (13 cases). The mean time interval to recurrence was 38.6 months, and the number of delayed recurred cases after 5 years was 10 ($22.2\%$). Of the clinicopathologic factors, depth of invasion, L/N metastasis, macroscopic type, lymphatic invasion, and vessel invasion, were significant risk factors in the univariate analysis. However, in the multivariate analysis, only L/N metastasis was an independent prognostic factor. Conclusion: Based on the results of this study, L/N metastasis is an independent prognostic factor. Thus, in patients with node-positive disease, adjuvant therapy might be considered, and long-term close follow-up might facilitate early detection and treatment of recurrent disease due to delayed recurrence.

• Journal of Gastric Cancer
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• v.12 no.3
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• pp.140-148
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• 2012

Purpose: Among cell adhesion molecules, serum levels of intercellular adhesion molecule-1 and E-selectin are known to be correlated with the metastatic potential of gastric cancer. In the present study, the authors investigated the expression of intercellular adhesion molecule-1 and E-selectin in gastric cancer tissues and cultured gastric cancer cells, and examined their clinical value in gastric cancer. Materials and Methods: The protein was extracted from gastric cancer tissues and cultured gastric cancer cells (MKN-28 and Kato-III) and the expression of intercellular adhesion molecule-1 and E-selectin was examined by western blotting. The clinical significance of intercellular adhesion molecule-1 and E-selectin was explored, using immunohistochemical staining of specimens from 157 gastric cancer patients. Results: In western blot analysis, the expressions of intercellular adhesion molecule-1 in gastric cancer tissues and cultured gastric cancer cells were increased, however, E-selectin in gastric cancer tissues and cells were not increased. Among 157 gastric cancer patients, 79 patients (50%) were intercellular adhesion molecule-1 positive and had larger tumor size, an increased depth of tumor invasion, lymph node metastasis and perineural invasion. The intercellular adhesion molecule-1 positive group showed a higher incidence of tumor recurrence (40.5%), and a poorer 3-year survival than the negative group (54.9 vs. 85.9%, respectively). Conclusions: Intercellular adhesion molecule-1 is overexpressed in gastric cancer tissues and cultured gastric cancer cells, whereas E-selectin is not overexpressed. Increased expression of intercellular adhesion molecule-1 in gastric cancer could be related to the aggressive nature of the tumor, and has a poor prognostic effect on gastric cancer.

• Journal of Gastric Cancer
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• v.20 no.2
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• pp.139-151
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• 2020

Purpose: Globally, there is a high incidence of gastric cancer (GC). Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is reported to play a vital role in several human malignancies. However, there is limited understanding of the role of LETM1 in GC. This study aims to investigate the effects of LETM1 on proliferation, migration, and invasion of GC cells. Materials and Methods: The expression levels of LETM1 in the normal gastric mucosal epithelial cells (GES-1) and GC cells were analyzed by quantitative real-time polymerase chain reaction and western blotting. CCK-8, wound healing, and Transwell invasion assays were performed to evaluate the effect of LETM1 knockdown or overexpression on the proliferation, migration, and invasion of the GC cells, respectively. Additionally, the effect of LETM1 knockdown or overexpression on GC cell apoptosis was determined by flow cytometry. Furthermore, the effect of LETM1 knockdown or overexpression on the expression levels of PI3K/Akt signaling pathway-related proteins was evaluated by western blotting. Results: The GC cells exhibited markedly higher mRNA and protein expression levels of LETM1 than the GES-1 cells. Additionally, the knockdown of LETM1 remarkably suppressed the GC cell proliferation, migration, and invasion, and promoted the apoptosis of GC cells, which were reversed upon LETM1 overexpression. Furthermore, the western blotting analysis indicated that LETM1 facilitates GC progression via the PI3K/Akt signaling pathway. Conclusions: LETM1 acts as an oncogenic gene to promote GC cell proliferation, migration, and invasion via the PI3K/Akt signaling pathway. Therefore, LETM1 may be a potential target for GC diagnosis and treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.3123-3128
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• 2014

The liver is normally the major site of glucose metabolism in intact organisms and the most important target organ for the action of insulin. It has been widely accepted that insulin resistance (IR) is closely associated with postoperative recurrence of hepatocellular carcinoma (HCC). However, the relationship between IR and drug resistance in liver cancer cells is unclear. In the present study, IR was induced in HepG2 cells via incubation with a high concentration of insulin. Once the insulin-resistant cell line was established, the stability of HepG2/IR cells was further tested via incubation in insulin-free medium for another 72h. Afterwards, the biological effects of insulin resistance on adhesion, migration, invasion and sensitivity to cis-platinum (DDP) of cells were determined. The results indicated that glucose consumption was reduced in insulin-resistant cells. In addition, the expression of the insulin receptor and glucose transportor-2 was downregulated. Furthermore, HepG2/IR cells displayed markedly enhanced adhesion, migration, and invasion. Most importantly, these cells exhibited a lower sensitivity to DDP. By contrast, HepG2/IR cells exhibited decreased adhesion and invasion after treatment with the insulin sensitizer pioglitazone hydrochloride. The results suggest that IR is closely related to drug resistance as well as adhesion, migration, and invasion in HepG2 cells. These findings may help explain the clinical observation of limited efficacy for chemotherapy on a background of IR, which promotes the invasion and migration of cancer cells.

• Journal of Life Science
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• v.16 no.6
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• pp.964-971
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• 2006

The cancer cells, characterized by local invasion and distant metastasis, are very dependant on extracellular matrix. The expression of matrix metalloproteinases (MMPs) has been implicated in the invasion and metastasis of cancer cells. Among the human MMPs, matirx metalloproteinase-2 (MMP-2) and matrix metalloproteinse-9 (MMP-9) are key enzymes that degrade type IV collagen of the matrix. Here, we studied the effect of disulfiram, an anti-tumor compound, on the suppression of the tumor invasion and the activity of MMP-2, MMP-9 in human osteosarcoma cells (U2OS). Disulfiram had the type IV collagenase inhibitory activity, the effect of inhibition of gene and protein expression, and these inhibitions were responsible for blocking invasion through cell mediated and non-cell mediated pathways. In conclusion, disulfiram inhibited expression of MMP-2 and MMP-9, and regulated the invasion of U2OS, Caki-1 and Caski. These observations raise the possibility of clinical therapeutic applications for disulfiram used as a potential inhibitor of cancer invasion.

• Journal of Life Science
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• v.21 no.7
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• pp.923-931
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• 2011

In the present study, we investigated the effect of indole-3-carbinol (I3C), a natural compound present in vegetables, on the cell migration and invasion of OVCAR-3 ovarian cancer cells. Our results indicated that I3C inhibited the proliferation of OVCAR-3 cells, a process which was associated with inhibition of cell motility as determined by wound healing experiments and cell invasion studies. I3C treatment increased the tightness of the tight junctions (TJs), which was demonstrated by an increase in transepithelial electrical resistance and a decrease in paracellular permeability. The RT-PCR and immunoblotting results indicated that I3C repressed the levels of claudin-3 as well as claudin-4, proteins that comprise a major part of TJs and play a key role in the control and selectivity of paracellular transport. Furthermore, the activities of matrix metalloproteinase (MMP)-2 and MMP-9 were also decreased by treatment with I3C, which was connected with the down-regulation of their mRNAs and protein expression. The results suggest that I3C may be expected to inhibit cancer cell metastasis and invasion by restoring TJs and decreasing MMP activity in ovarian cancer cell line OVCAR-3.

• Journal of Gastric Cancer
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• v.14 no.2
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• pp.111-116
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• 2014

Purpose: The standard surgical procedure recommended to treat gastric cancer in advanced cases is dissection of D2 lymph nodes (LNs). However, the optimum number of LNs that should be retrieved in advanced gastric cancer (AGC) remains debatable. Therefore, this study aimed to investigate the optimum number of retrieved LNs and determine the clinical implications of retrieved LN numbers on the treatment of AGC. Materials and Methods: Of 575 AGC patients reviewed, 369 who underwent open curative gastrectomy with D2 or more extensive LN dissection at our institution were analyzed according to their clinicopathologic characteristics and number of LNs retrieved. Results: Multivariate regression analysis revealed that tumor size (P=0.006), depth of invasion (P=0.000), LN metastasis (P=0.000), and stage (P=0.000) were independent variables with predictive value. The 5-year survival rates were differed significantly according to the numbers of LNs retrieved ([1] 15~25 vs. >25 and [2] 15~39 vs. ${\geq}40$) in patients with differentiated carcinoma. Conclusions: Tumor size, depth of invasion, LN metastasis, and stage were independent predictive factors for survival. The number of retrieved LNs was significantly associated with a long-term survival benefit in patients with differentiated carcinoma. Therefore, our data suggest that the retrieval of a minimum of 15 LNs may not be sufficient to warrant a recommendation for further curative surgery and that extensive LN dissection should be considered in advanced carcinoma of the differentiated type.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.553-556
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• 2013

Background: This study was designed to examine changing trends in localization of gastric cancer in Turkey in recent years. Materials and Methods: A total of 796 adult patients with newly diagnosed, histologically proven adenocarcinomas, treated and followed up at our oncology center between 2000-2011, were examined retrospectively. In all cases tumor localization were identified and recorded with clinicopathological features. Results: The median age was 58 with a range between 22-90 for the 552 men and 244 women. Median follow up was 12 months (1-276) and median overall survival was also 12 months (11.5-12.4). There was a trend for a change in tumor localization from distal to proximal. Survival of patients was low with advanced T and N stage tumours. Positive surgical margins, lymphovascular invasion, perineural invasion, cardioesophageal localization were predisposition factors for metastatic disease in gastric cancer. There was no relation between age or sex and histopathological type of gastric cancer. Conclusions: There is a trend in our country for a change in gastric tumour localization from distal to proximal, with clear significance for treatment choices.

• Journal of Gastric Cancer
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• v.12 no.3
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• pp.164-172
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• 2012

Purpose: The purpose of this study is to investigate the prognostic significance of tumor size for 5-year survival rate in patients with gastric cancer. Materials and Methods: A total of 1,697 patients with gastric cancer, who underwent potentially curative gastrectomy, were evaluated. Patients were divided into 4 groups as follows, according to the median size of early and advanced gastric cancer, respectively: small early gastric cancer (tumor size ${\leq}3$ cm), large early gastric cancer (tumor size >3 cm), small advanced gastric cancer (tumor size ${\leq}$ 6 cm), and large advanced gastric cancer (tumor size >6 cm). The prognostic value of tumor size for 5-year survival rate was investigated. Results: In a univariate analysis, tumor size is a significant prognostic factor in advanced gastric cancer, but not in early gastric cancer. Multivariate analysis showed that tumor size is an independent prognostic factor for 5-year survival rate in advanced gastric cancer (P=0.003, hazard ratio=1.372, 95% confidence interval=1.115~1.690). When advanced gastric cancer is subdivided into 2 groups, according to serosa invasion: Group 1; serosa negative (T2 and T3, 7th AJCC), and Group 2; serosa positive (T4a and T4b, 7th AJCC), tumor size is an independent prognostic factor in Group 1 (P=0.011, hazard ratio=1.810, 95% confidence interval=1.149~2.852) and in Group 2 (P=0.033, hazard ratio=1.288, 95% confidence interval=1.020~1.627), respectively. Conclusions: Tumor size is an independent prognostic factor in advanced gastric cancer irrespective of the serosa invasion, but not in early gastric cancer.