Biomedical subjects

Woo Ho Kim

Publications and source records attributed to Woo Ho Kim.

At least 37 records · Page 2Linked to original sources

PubMed2005

Clinicopathologic and protein expression differences between cardia carcinoma and noncardia carcinoma of the stomach.

BACKGROUND: Although the incidence of adenocarcinoma of the stomach has decreased over the past several decades, gastric cardia carcinoma has increased over the same period. METHODS: The clinicopathologic characteristics and immunohistochemical staining results of 21 proteins were investigated in 165 patients with cardia carcinoma, including 74 patients with true cardia carcinoma and 91 patients with subcardia carcinoma, and the results were compared with the results from 564 patients with noncardia carcinoma. RESULTS: In the clinicopathologic analysis, patients who had cardia carcinoma tended to have tumors with poorly differentiated histology according to the World Health Organization classification system (P = 0.012), diffuse type according to the Lauren classification system (P = 0.049), and advanced pathologic TNM stage (P < 0.001). On immunohistochemical staining, loss of the p16 (P = 0.038) and smad4 (P < 0.001) tumor suppressor genes was more frequent in cardia carcinoma than in noncardia carcinoma. Carcinoembryonic antigen and CD44 overexpression were more frequent in patients with cardia carcinoma (P < 0.05). Conversely, patients who had cardia carcinoma exhibited less frequent expression of MUC1 (P = 0.008) and MUC5AC (P = 0.006) compared with patients who had noncardia carcinoma. Epstein-Barr virus infection was more common in patients with cardia carcinoma (P < 0.001). In the survival analysis, the patients with cardia carcinoma had a poorer prognosis. In the multivariate analysis, tumor location in the cardia was confirmed as an independent, poor prognostic factor in patients with gastric carcinoma. CONCLUSION: Cardia carcinoma and noncardia carcinoma differed in their clinicopathologic characteristics and in their alterations of gene expression, as evaluated by immunohistochemistry. The current results support the hypothesis that cardia carcinoma forms a specific category of gastric carcinoma that is distinct from noncardia carcinoma.

Carcinoma↗

PubMed2005

Nuclear factor-kappaB activation correlates with better prognosis and Akt activation in human gastric cancer.

PURPOSE: Because the biological significance of constitutive nuclear factor-kappaB (NF-kappaB) activation in human gastric cancer is unclear, we undertook this study to clarify the regulatory mechanism of NF-kappaB activation and its clinical significance. EXPERIMENTAL DESIGN: Immunohistochemistry for NF-kappaB/RelA was done on 290 human gastric carcinoma specimens placed on tissue array slides. The correlations between NF-kappaB activation and clinicopathologic features, prognosis, Akt activation, tumor suppressor gene expression, or Bcl-2 expression were analyzed. We also did luciferase reporter assay, Western blot analysis, and reverse transcription-PCR using the SNU-216 human gastric cancer cell line transduced with retroviral vectors containing constitutively active Akt or the NF-kappaB repressor mutant of IkappaBalpha. RESULTS: Nuclear expression of RelA was found in 18% of the gastric carcinomas and was higher in early-stage pathologic tumor-node-metastasis (P = 0.019). A negative correlation was observed between NF-kappaB activation and lymphatic invasion (P = 0.034) and a positive correlation between NF-kappaB activation and overall survival rate of gastric cancer patients (P = 0.0228). In addition, NF-kappaB activation was positively correlated with pAkt (P = 0.047), p16 (P = 0.004), adenomatous polyposis coli (P < 0.001), Smad4 (P = 0.002), and kangai 1 (P < 0.001) expression. An in vitro study showed that NF-kappaB activity in gastric cancer cells is controlled by and controls Akt. CONCLUSIONS: NF-kappaB activation was frequently observed in early-stage gastric carcinoma and was significantly correlated with better prognosis and Akt activation. These findings suggest that NF-kappaB activation is a valuable prognostic variable in gastric carcinoma.

Adolescent↗

PubMed2005

Multicenter analysis of clinicopathologic features of intraductal papillary mucinous tumor of the pancreas: is it possible to predict the malignancy before surgery?

BACKGROUND: Despite recently increasing numbers of reports on intraductal papillary mucinous tumors (IPMTs), difficulties still remain in terms of diagnosis, treatment, and prognosis. The purpose of this multicenter study was to evaluate the clinicopathologic features of IPMT in Korea and to suggest predictive criteria for malignancy in IPMT. METHODS: We retrospectively reviewed the clinicopathologic data of 208 patients who underwent operations for IPMT between 1993 and 2002 at 28 institutes in Korea. RESULTS: Of the 208 patients (mean age, 61 years), 147 were men and 61 were women. A total of 124 patients underwent pancreatoduodenectomy, 42 underwent distal pancreatectomy, 17 underwent total pancreatectomy, and 25 underwent limited pancreatic resection. There were 128 benign cases (adenoma, n = 62; borderline, n = 66) and 80 malignant cases (noninvasive, n = 29; invasive, n = 51). A significant difference in 5-year survival was observed between the benign and malignant groups (92.6% vs. 65.3%; P = .006). Of the six factors (age, location, duct dilatation, mural nodule, main duct type, and tumor size) that showed statistical differences by univariate analysis between the benign and malignant groups, three were significant by multivariate analysis--namely, mural nodule (P = .009), tumor size (P = .023), and a dilated duct size (P = .010). CONCLUSIONS: A significant proportion of IPMTs are malignant, although the overall prognosis of IPMT is superior to that of ordinary pancreatic cancer. Radical surgery is recommended for IPMT with the predictors of malignancy: mural nodule, tumor size (> or =30 mm), and dilated duct size (> or =12 mm).

Adenocarcinoma, Mucinous↗

PubMed2005

Tumor budding as an indicator of isolated tumor cells in lymph nodes from patients with node-negative colorectal cancer.

PURPOSE: Isolated tumor cells are often found in the regional lymph nodes of colorectal cancer, although their prognostic significance has not been established yet. This study was performed to investigate the correlation between the presence of isolated tumor cells in lymph nodes and the histopathologic characteristics of colorectal cancers and, thus, to determine which factors are associated with isolated tumor cells. METHODS: We used immunohistochemistry with anticytokeratin antibody to examine 2,784 lymph nodes in 109 patients with node-negative colorectal cancers. The clinicopathologic features of the tumors with isolated tumor cells were compared with those without isolated tumor cells. The frequency, number, and level of the isolated tumor cells also were assessed. RESULTS: Isolated tumor cells were detected in 335 lymph nodes (12 percent) from 71 patients (65.1 percent). Those tumors having isolated tumor cells in lymph nodes, compared with those not having isolated tumor cells, were characterized by large tumor size, high T stage (pT3 and pT4), angiolymphatic invasion, perineural invasion, absence of peritumoral lymphocytic response, microsatellite instability-negative phenotype, and tumor budding. Multivariate analysis showed that those factors independently associated with the presence of isolated tumor cells were high T stage, tumor budding, and microsatellite instability-negative phenotype. Among the 71 patients with high T stage and microsatellite instability-negative phenotype, tumors with isolated tumor cells were characterized by a high frequency of tumor budding compared with tumors without isolated tumor cells (85 vs. 36.4 percent). In a further study, the degree of budding, which was assessed by an immunohistochemical study of gamma2 chain of laminin-5, was closely related to the number and location of isolated tumor cells. Moreover, we found that most of the isolated tumor cells in the regional lymph nodes also expressed gamma2 chain of laminin-5. CONCLUSIONS: Our results suggested that isolated tumor cells are derived from undifferentiated cancer cells or small clusters ("budding") at the invasive front. Thus, tumor budding may be used as an indicator of isolated tumor cells in lymph nodes with node-negative colorectal cancers.

Adult↗

PubMed2005

Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers.

The aim of the current study was to evaluate the protein expression involved in the progression from dysplasia to invasive esophageal squamous cell carcinomas and to analyze the prognostic value of markers. Immunohistochemistry was performed for cell cycle regulators [p53, p21, p27, p16, cyclin D1, Rb], apoptosis-related proteins [Fas, Fas-L, FADD, TRAIL, DR4, DR5, caspase-8, caspase-3, bcl-2, Bax], tumor suppressor proteins [beta-catenin, E-cadherin, FHIT, Smad 4, VHL, PTEN, KAI-1], and oncoproteins [c-myc, COX-2, EGFR]. Caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR revealed significant differences between dysplasia and their corresponding invasive cancer portion in 25 cases. In a total of 118 cases of invasive cancer, proteins with frequent (> or = 60% of the cases) alterations were p53 (overexpression in 64% of SCCs), p27 (loss in 91%), p16 (loss in 81%), and FHIT (loss in 75%). Early clinical stage and bcl-2 immunopositivity were related to the survival rate of patients. In conclusion, caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR may be involved in the progression from dysplasia to invasive esophageal SCCs. Clinical stage and bcl-2 are independent prognostic factors throughout the multivariate analysis.

Adult↗

PubMed2005

Clinicopathologic analysis of early ampullary cancers with a focus on the feasibility of ampullectomy.

OBJECTIVE: The purpose of this study was to evaluate whether ampullectomy can substitute for pancreatoduodenectomy (PD) in early ampullary cancer by clinicopathologic study. SUMMARY BACKGROUND DATA: Although ampullectomy has been attempted in early ampullary cancer (pTis, pT1), the indication and extent of resection have not been established. METHODS: Of 201 patients who had undergone PD for ampullary cancer between 1986 and 2002, 67 patients with a histologic diagnosis of pTis (n = 5) or pT1 (n = 62) cancer were analyzed retrospectively. Pathologic PD specimens were reviewed to analyze the cancer spread pattern, and medical records were reviewed for clinical outcomes. RESULTS: The 5-year survival rate of the 66 patients with early ampullary cancer (excluding one mortality) was 83.7%. Recurrence was confirmed in 12 patients (18.2%) and all died because of the recurrence. Pathologic review showed that 22 patients (32.8%) had at least one risk factor for failure after ampullectomy: lymph node metastasis (n = 6, 9.0%), perineural invasion (n = 1), or mucosal tumor infiltration along the CBD or P-duct (n = 15, 22.4%). Mean lengths of invasion into the CBD or the P-duct beyond the sphincter of Oddi were 7.7 mm (range, 1-25 mm) or 6.3 mm (range, 2-18 mm), respectively. Moreover, these risk factors were not correlated with tumor size, histologic grade, or the gross morphology of the primary tumor, although pTis cancer or pT1 cancer sized 1.0 cm or less was found to be least associated with risk factors. CONCLUSIONS: Ampullectomy for early ampullary cancer should not be considered an alternative operation to PD because of the high possibility of recurrence. PD should be preferably performed for adequate radical resection, even in early ampullary cancer, and ampullectomy should be reserved for those who have pTis or pT1 cancer sized 1.0 cm or less with high operative risk.

Adult↗

PubMed2005

Loss of caspase-1 gene expression in human gastric carcinomas and cell lines.

The caspases are a family of aspartic acid-specific proteases that fulfill varied and often critical roles in mammalian apoptosis or in the proteolytic activation of cytokines. Caspase-1 (interleukin-1beta-converting enzyme) is a member of the cysteine protease family, which cleaves target proteins following aspartic acid residues. We investigated caspase-1 expression in stomach cancer, tissues and cell lines. Of 301 consecutive gastric carcinomas, 58 cases (19.3%) showed the expressional loss of caspase-1. Loss of caspase-1 expression was significantly associated with pTNM stage (p=0.03), lymph node metastasis (p=0.01) and patient survival (p<0.01). Caspase-1 expression was also significantly correlated in an inverse manner with p53 expression (p<0.01). Among the 11 gastric cancer cell lines examined, three cell lines showed loss of expression at the protein and mRNA levels. On treatment with 5-aza-2'-deoxycytidine (5-aza-C), and/or trichostatin A (TSA), all three cell lines re-expressed caspase-1 mRNA. The above findings suggest that epigenetic events such as DNA methylation and histone deacetylation play important roles in the regulation of caspase-1, and that loss of caspase-1 expression is associated with poor survival in gastric carcinoma.

Antimetabolites, Antineoplastic↗

PubMed2005

Growth effect of gastrin on gastric cancer and its clinical implications for gastric cancer surgery.

This study was aimed at investigating the effect of gastrin on the growth of gastric cancer and evaluating postoperative hypergastrinemia in patients that had received various types of gastrectomy for gastric cancer. RT-PCR for gastrin/CCKB receptor mRNA was performed in human gastric cancer cell lines and tissue. The effect of gastrin or glycine-extended gastrin on the growth of gastric cancer cell lines was determined by MTT assay. Serum gastrin levels were compared with respect to the resection type of gastric cancer surgery. Gastrin/CCKB receptor mRNA expression was detected in all 9 gastric cancer cell lines, and in 19 of 29 (62%) gastric cancer tissue samples. Growth of gastric cancer cell lines containing the gastrin/CCKB receptor was significantly enhanced by gastrin and glycine-extended gastrin. The proximal gastrectomy group had a significantly higher mean serum gastrin level than the distal subtotal gastrectomy, total gastrectomy, or preoperative groups (p<0.05). Our study confirms that a high proportion of gastric cancer tissue samples express the gastrin/CCKB receptor, which can stimulate the growth of gastrin/CCKB receptor-positive gastric cancer cells. In addition, we confirm that hypergastrinemia can be induced in about half of patients after proximal gastrectomy. More studies are needed to clarify the relationship between hypergastrinemia and tumor recurrence after proximal gastrectomy.

Cell Line, Tumor↗

PubMed2005

Cell-cycle regulators, bcl-2 and NF-kappaB in Epstein-Barr virus-positive gastric carcinomas.

The mechanism by which Epstein-Barr virus (EBV) contributes to the carcinogenesis of gastric mucosa remains unanswered. In this study, the role of cell-cycle regulators (p53, p21, p27, p16, cyclin D1, Rb), bcl-2 and NF-kappaB p65 (Rel A) was evaluated. Immunohistochemistry for these proteins was performed in EBV-positive (n=55) and EBV-negative gastric carcinomas (n=72). The bcl-2 protein by western blot and EBV transcripts using RT-PCR were studied in cell lines. The p27 loss, p16 loss, cyclin D1 expression and NF-kappaB nuclear positivity were more frequent in EBV-positive gastric carcinomas than those in EBV-negative gastric carcinomas, while p53 overexpression seldom occurred in EBV-positive carcinomas (p<0.001). EBV-positive gastric carcinoma showed unique p53 immunostaining (heterogeneous, weak to moderate, focal staining), and rare bcl-2 positivity (1 case). Western blot showed bcl-2 to be irrespective of EBV status in stomach cancer cell lines. However, bcl-2 was highly expressed in EBV-positive lymphoma or EBV-positive lymphoblastoid cell lines. The BARF1 transcript was confirmed in both EBV-positive stomach cancer and EBV-positive lymphoma, suggesting tissue type-specific bcl-2 activation by BARF1. The pathological tumor stage was the only independent prognostic factor. A small size of tumor, p16 preservation and NF-kappaB nuclear positivity were associated with a good prognosis in univariate analysis (p<0.05). p27, p16, cyclin D1 and NF-kappaB may be associated with oncogenesis in EBV-positive gastric carcinomas. EBV-positive gastric carcinomas showed infrequent p53 overexpression, wild-type p53 stabilization and rare bcl-2 involvement. The characteristic expression of proteins may relate to both EBV and tissue type.

Adolescent↗

PubMed2004

Prognostic significance of microsatellite instability in sporadic colorectal cancer.

BACKGROUND AND AIMS: Colorectal cancers exhibiting microsatellite instability (MSI) appear to have unique biological behavior. The influence of MSI on the prognosis of sporadic colorectal cancers is controversial and requires further investigation. The aim of this study was to analyze the association between MSI status and clinicopathological features and prognosis in sporadic colorectal cancer patients. PATIENTS AND METHODS: Of the 322 consecutive colorectal cancer patients operated upon at the Seoul National University Hospital between January and December 1998, we examined the clinicopathological features and prognosis of 248 patients with sporadic primary colorectal cancer. The MSI status of these 248 patients has been reported in a previous study. Of the 248 patients, 23 (9.3%) had MSI+ tumors. The patients' clinicopathological parameters were obtained from their medical records, and follow-up and survival data were obtained from medical records and phone calls. RESULTS: MSI+ sporadic colorectal cancers were found predominantly in the proximal colon ( p<0.001) and were associated with poor differentiation ( p=0.030), a lower preoperative serum carcinoembryonic antigen (CEA) level ( p=0.012), and less frequent systemic metastasis ( p=0.034) than MSI- tumors. Low tumor grade ( p=0.022), low tumor T-stage ( p=0.002), no lymph node metastasis ( p<0.001), no systemic metastasis ( p<0.001), adjuvant chemotherapy ( p<0.001) and MSI+ status ( p=0.038) were independent favorable prognostic factors for survival in sporadic colorectal cancer patients. CONCLUSION: MSI status was an independent favorable prognostic factor for survival in sporadic primary colorectal cancer patients.

Adult↗

PubMed2004

A naturally derived gastric cancer cell line shows latency I Epstein-Barr virus infection closely resembling EBV-associated gastric cancer.

In a process seeking out a good model cell line for Epstein-Barr virus (EBV)-associated gastric cancer, we found that one previously established gastric adenocarcinoma cell line is infected with type 1 EBV. This SNU-719 cell line from a Korean patient expressed cytokeratin without CD19 or CD21 expression. In SNU-719, EBNA1 and LMP2A were expressed, while LMP1 and EBNA2 were not. None of the tested lytic EBV proteins were detected in this cell line unless stimulated with phorbol ester. EBV infection was also shown in the original carcinoma tissue of SNU-719 cell line. Our results support the possibility of a CD21-independent EBV infection of gastric epithelial cells in vivo. As the latent EBV gene expression pattern of SNU-719 closely resembles that of the EBV-associated gastric cancer, this naturally derived cell line may serve as a valuable model system to clarify the precise role of EBV in gastric carcinogenesis.

Adenocarcinoma↗

PubMed2004

Epstein-barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with epstein-barr virus-negative carcinoma.

PURPOSE: EBV has been detected in 2-16% of gastric carcinomas. However, there is little information available about the gene expression profile of EBV-positive gastric carcinomas. EXPERIMENTAL DESIGN: EBV infection was examined using EBV-encoded small RNAs (EBERs) in situ hybridization, and 63 (5.6%) of 1127 consecutive gastric carcinomas were found to be EBV-positive. The expressions of 27 tumor-associated proteins were evaluated immunohistochemically in 63 EBV-positive gastric carcinomas and 287 EBV-negative carcinomas using the tissue array method. In addition, the genotype of EBV was investigated by PCR amplification of LMP1 (latent membrane protein 1), Epstein-Barr nuclear antigen 2 (EBNA2), and EBNA3B genes. RESULTS: EBV-positive gastric carcinomas are characterized by the presence of lymphoid stroma, proximal location, and predominance in males. In comparison with EBV-negative carcinomas, EBV-positive carcinomas showed frequent loss of expression of p16, smad4, FHIT, and KAI-1 (kangai 1; P < 0.05), but retained the expression of APC (adenomatous polyposis coli), DCC (deleted in colorectal cancer), and some DNA repair proteins (P < 0.05). There was negative association between EBV infection and the expression of MUC1, MUC2, MUC5AC, p53, CEA, C-erbB2, and smad7. Using hierarchical cluster analysis, we divided EBV-positive gastric carcinomas into two clusters. Those patients with cluster 1 (42 cases) carcinomas had a better prognosis than those with cluster 2 (12 cases; P = 0.0002) or those with EBV-negative carcinomas (280 cases; P = 0.0251). Fifty-one (92.7%) of 55 EBV-positive carcinomas demonstrated the 30-bp deletion in LMP1 gene, and 53 (96.4%) of 55 cases were type 1 for EBNA2 and EBNA3B genes. CONCLUSION: EBV-positive gastric carcinomas have a distinct protein expression profile as well as distinct clinicopathological features, as compared with EBV-negative carcinomas. The subclassification of EBV-positive carcinomas, by hierarchical cluster analysis, is significantly associated with patient survival.

Base Sequence↗

PubMed2004

Cytokeratin expression profile in gastric carcinomas.

Cytokeratin (CK) is observed mainly in epithelial cells, and the diverse expression pattern of CK subtypes may be helpful in discriminating between primary and metastatic carcinomas in various organs, including the stomach. To clarify the CK expression profiles in gastric carcinomas, 329 consecutive specimens were immunohistochemically evaluated in terms of their CK subtypes using the tissue array method. The overall positive rates were 84.7% for CK4, 3.2% for CK5, 28.7% for CK6, 71.1% for CK7, 96.6% for CK8, 0% for CK10, 81.6% for CK13, 0.3% for CK14, 4.1% for CK16, 0% for CK17, 99.4% for CK18, 89.7% for CK19, and 30.0% for CK20. Well-differentiated or moderately differentiated carcinomas were related to several CKs, and mucinous carcinoma was associated with CK20 expression. Interestingly, CK7 and CK20 expression was associated with the mucin phenotype of gastric carcinoma, but this association had no diagnostic value. Epstein-Barr virus (EBV)-associated gastric carcinomas showed a tendency toward negative expression of CK7. CK6 expression was related to microsatellite instability (MSI), early pTNM stage, and better clinical outcome. In conclusion, CK expression profiles in consecutive gastric carcinomas demonstrate heterogeneity, and no single CK has diagnostic value by itself. CK expression is associated with various clinicopathologic parameters, mucin phenotype, EBV positivity, MSI status, and patient survival.

Biomarkers, Tumor↗

PubMed2004

Overexpression of clusterin in human hepatocellular carcinoma.

Clusterin has been reported to play a significant role in tumorigenesis, and its overexpression occurs in various human malignancies. We examine the clusterin overexpression in human hepatocellular carcinoma (HCC) and verify its clinical usefulness as a candidate biomarker by clinicopathologic and survival analysis. We examined clusterin overexpression immunohistochemically in 100 surgically resected HCCs using the tissue microarray method. A total of 89 HCCs exhibited clusterin overexpression, in 2 distinct staining patterns, cytoplasmic (n=35) and canalicular (n=54). Clusterin positivity demonstrated an inverse correlation with tumor cell apoptosis evaluated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay (P=0.024). Within the clusterin-positive group, cytoplasmic overexpression had a positive correlation with tumor cell proliferative activity measured by the Ki-67 labeling index (P=0.003). HCCs demonstrating cytoplasmic clusterin overexpression were associated with poor Edmondson's histological grade and high TNM stage (P <0.05). In the survival analysis, the cytoplasmic-positive group demonstrated an overall poorer prognosis than the canalicular-positive group, according to univariate and multivariate analysis (P <0.05). In HCC, clusterin may play an important role in tumorigenesis and progression, corresponding to its subcellular localization. Cytoplasmic clusterin overexpression could be a potential new prognostic marker for the aggressiveness of HCC.

Apoptosis↗

PubMed2004

Phenotypic alterations of mucins and cytokeratins during gallbladder carcinogenesis.

In order to evaluate the significance of altered expression of mucin and cytokeratin during gallbladder carcinogenesis, we characterized the expressional profiles of MUC1, MUC2, MUC5AC, MUC6, CK7 and CK20 in 33 normal mucosa, 31 adenomas, 55 dysplasias and 131 carcinomas of the gallbladder. In normal gallbladder mucosa, the expressions of MUC5AC and MUC6 were diffuse and MUC1 expression was absent. However, in adenomas, dysplasias and carcinomas, the expressions of MUC5AC and MUC6 tended to decrease, whereas MUC1 expression was elevated. MUC2 and CK20 were infrequently expressed in all of the gallbladder epithelia, but adenomas expressing MUC2 and/or CK20 were more frequently associated with carcinomas and showed a higher grade of atypia than those without these antigens. In carcinomas, MUC1 expression was related to invasive growth, lymph node metastasis and a non-papillotubular type, whereas MUC6 expression was related to non-invasive growth. CK7 was diffusely expressed in almost all lesions, but carcinomas with a loss of CK7 expression showed poor survival. In conclusion, normal gallbladder mucosa has a gastric phenotype, but during carcinogenesis and tumor progression, the gastric phenotype is gradually lost and the aberrant expression of MUC1 occurs. The intestinal phenotype is not common in the gallbladder.

Adenoma↗

PubMed2003

Manganese superoxide dismutase expression correlates with chemosensitivity in human gastric cancer cell lines.

PURPOSE: The purpose is to investigate the potential correlation between antioxidant enzyme (AOE) levels and resistance to anticancer drugs in human gastric carcinoma cell lines. EXPERIMENTAL DESIGN: Protein contents of AOEs such as manganese superoxide dismutase (MnSOD), copper/zinc superoxide dismutase, catalase, glutathione S-transferase-pi, p-glycoprotein, and multidrug resistance-associated protein were observed by Western blot analysis, and MnSOD activity was measured in six Korean gastric cancer cell lines. The direct correlation between AOEs and the chemosensitivity to doxorubicin (DOX), mitomycin C, 5-fluorouracil, and vinblastine was analyzed by cytotoxicity test. MnSOD was overexpressed by transient transfection of human MnSOD cDNA. RESULTS: Expressions of AOEs in gastric cancer cell lines were variable. MnSOD expression was related with the resistance to DOX and mitomycin C but not with that to 5-fluorouracil and vinblastine. In comparison, expressions of other AOEs, p-glycoprotein and multidrug resistance-associated protein, were not correlated with tumor sensitivity to any of the drugs used. Cell lines with a high MnSOD protein content showed higher MnSOD activity than those with a low MnSOD protein content. In addition, MnSOD overexpression increased the resistance of gastric carcinoma cells to DOX. CONCLUSIONS: MnSOD is an important factor of drug response to reactive oxygen species-generating anticancer drugs in the gastric cancer cells. Thus, measurement of MnSOD levels in clinical samples may provide an indication of subsequent treatment response of gastric cancer patients.

Antineoplastic Agents↗

PubMed2003

Aberrant methylation of the specific CpG island portion regulates cyclooxygenase-2 gene expression in human gastric carcinomas.

Although it has been well established that overexpression of cyclooxygenase-2 (Cox-2) favors tumorigenesis and metastasis, the molecular mechanism that regulates Cox-2 expression has not been well defined in gastric carcinoma. Aberrant methylation of the CpG island is known to be one of the powerful mechanisms for the suppression of gene expression, and usually, CpG islands are very rich in promoter region and exon-1 region. But, it is controversial whether Cox-2 gene expression is regulated by methylation of promoter region or exon-1 region. In this study, we examined whether the hyper-methylation mediated transcriptional silencing of Cox-2 also occurred in human gastric carcinoma tissues and which portion of CpG island methylation is important in Cox-2 gene expression. Genomic DNAs from human gastric carcinoma tissues were treated with three methylation-sensitive restriction enzymes and then Southern blot analysis was performed. Out of 30 primary gastric tumor samples, 26 cases (86.6%) showed overexpression of Cox-2. Four cases (13.3%) with relatively decreased Cox-2 gene expression were associated with the presence of aberrant methylation of Cox-2 CpG island. We also found that methylation of promoter region and not exon-1 region is related with the transcriptional silencing of Cox-2 in gastric carcinoma cancer by detailed methylation mapping using bisulfite sequencing analysis. Our results suggest that the DNA methylation-mediated transcriptional silencing of Cox-2 is a predominant mechanism for the down-regulation of Cox-2 expression in human gastric carcinoma. Furthermore, the results suggest that methylation of not exon-1 region but promoter region is important to regulation of Cox-2 gene expression.

Blotting, Southern↗

PubMed2003

Prognostic significance of Bcl-2 and p53 expression in gastric cancer.

BACKGROUND AND AIMS: Apoptosis regulates cell death and influences cell proliferation and therefore may play an important role in development or growth of various malignant tumors. The Bcl-2 and p53 are closely linked in the regulation of apoptosis. We investigated the prognostic significance of Bcl-2 and p53 expression in patients with gastric cancer. PATIENTS AND METHODS: Immunohistochemistry was used to study Bcl-2 and p53 expression in 308 consecutive patients with gastric cancer. RESULTS: Bcl-2 expression was positive in 39 patients (12.7%) and showed a significant negative correlation with depth of invasion and lymph node metastasis. p53 expression was observed in 105 patients (34.1%) and was significantly associated with depth of invasion, lymph node metastasis, distant metastasis, and intestinal type. Patients with Bcl-2(+) tumors showed a trend to better 5-year survival rate (81%) than those with Bcl-2(-) negative tumors (71%). The 5-year survival rate in p53 positive cases (60%) was significantly lower than that in p53-negative cases (78%). In addition, p53 expression showed a significantly poorer prognosis in both diffuse and intestinal types. In multivariate analysis restricted to patients with R0 resection p53 expression was an independent prognostic factor (relative risk: 2.063). In combined assessment of p53 and Bcl-2 expression the group with p53(+)/Bcl-2(-) tumors showed significantly worse 5-year survival (57%) than the other groups, while best survival was seen in the group with p53(+)/Bcl-2(+) tumors (100%). CONCLUSION: p53 expression is an unfavorable prognostic factor in gastric cancer. Bcl-2 expression may have possible prognostic value when combined with p53 expression.

Adult↗