Different Pattern of Allelic Loss in Epstein-Barr Virus-Positive Gastric Cancer with Emphasis on the p53 Tumor Suppressor Pathway

Rees, Bastiaan P. van; Caspers, Eric; Hausen, Axel zur; Brule, Adriaan van den; Drillenburg, Paul; Weterman, Marian A. J.; Offerhaus, G. Johan A.

doi:10.1016/s0002-9440(10)64397-0

Cited by 42 publications

(35 citation statements)

References 24 publications

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“…The SMAD4 gene is located on chromosome region 18q21, and LOH in this region has been reported in 33% to 42% of gastric carcinomas (27,38). A summary of SMAD4 LOH and a comparison of chromosome 18q21 microsatellite markers are presented in Supplementary Table S5.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

Wang

Kim

Lee

et al. 2007

Clinical Cancer Research

101

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Purpose: Mothers against decapentaplegic homologue 4 (SMAD4) is a tumor suppressor gene associated with gastrointestinal carcinogenesis. The aim of the present study is to more precisely characterize its role in the development and progression of human gastric carcinoma. Experimental Design: The expression of SMAD4 was investigated in 283 gastric adenocarcinomas and related lesions, as well as in 9 gastric carcinoma cell lines. We also analyzed the methylation status of SMAD4 gene by using methylation-specific PCR, examined loss of heterozygosity (LOH) of this gene locus by using a vicinal marker, and detected exon mutation of SMAD4 through exon-by-exon amplification. Moreover, we assessed whether MG132, a proteasome inhibitor, affected the SMAD4 protein level. Results: We found loss of SMAD4 protein expression in the cytoplasm (36 of 114, 32%) and in the nucleus (46 of 114, 40%) of gastric cancer cells. The loss of nuclear SMAD4 expression in primary tumors correlated significantly with poor survival, and was an independent prognostic marker in multivariate analysis.We also found a substantial decrease in SMAD4 expression at both the RNA and protein level in several human gastric carcinoma cell lines. In addition, we found that LOH (20 of 70, 29%) and promoter hypermethylation (4 of 73, 5%) were associated with the loss of SMAD4 expression. SMAD4 protein levels were also affected in certain gastric carcinoma cell lines following incubation with MG132. Conclusion: Taken together, our results indicate that the loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. The loss of SMAD4 in gastric carcinomas was due to several mechanisms, including LOH, hypermethylation, and proteasome degradation.

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Section: Discussionmentioning

confidence: 99%

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

Wang

Kim

Lee

et al. 2007

Clinical Cancer Research

101

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“…have distinct molecular characteristics, as well as clinicopathological characteristics (5)(6)(7)(8). The loss of p16 protein is commonly associated with epigenetic mechanisms and is more common in EBV-infected tumors arising in the body of the stomach (24,25).…”

Section: Discussionmentioning

confidence: 99%

“…However, little is known regarding the molecular characteristics of EBV-positive gastric carcinomas. Recent studies suggest that hypermethylation of CpG islands is a mechanism of tumor suppressor gene silencing in EBV-positive gastric carcinomas (5), but allelic loss at some markers such as 5q [APC (adenomatous polyposis coli)], 17p (p53), and 18q (smad4) is inversely correlated with EBV positivity (6). The p53 tumor suppressor pathway (7) and microsatellite instability, a hallmark of a defective DNA mismatch-repair system (8), are not encountered in EBV-positive gastric carcinomas.…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus-Positive Gastric Carcinoma Has a Distinct Protein Expression Profile in Comparison with Epstein-Barr Virus-Negative Carcinoma

Lee¹,

Chang²,

Yang

et al. 2004

Clinical Cancer Research

112

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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 tumorassociated 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 EBVnegative 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;

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“…Our previous clinic paired comparative studies suggested that NM-3 had therapeutic effects on advanced gastric cancer. It could increase the surviving period of the patients, improve the life quality and increase the metastasis and recurrence after operation because of its lower toxic side-effect compared with intravenous chemical therapy [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] . Up to date, the effect of NM-3 on human gastric cancer has not been reported in the world.…”

Section: Discussionmentioning

confidence: 99%

Molecule action mechanisms of NM-3 on human gastric cancer SGC-7901 cellsin vivoorin vitro

Zhu

Shen²,

Chen³

et al. 2003

WJG

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AIM:To study the molecule action mechanisms of NM-3 on the growth of human gastric cancer SGC-7901 cells in vivo or in vitro.METHODS: SGC-7901 from human non-differentiated gastric cancer cell line was cultured with NM-3 at 100 mg/ml for 24 h. We observed its inhibitory rate and the density of micro-vascular growth in grafted mice with human gastric cancer SGC-7901. The apoptosis of human gastric cancer SGC-7901 was revealed in NM-3 treatment group by using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-fluorescene nick end labeling (TUNEL) method and flow cytometry analysis. RESULTS:The growth of SGC-7901 cells was markedly inhibited compared with control growp, which was smaller than that in normal saline control group (4.17 g±0.22 g vs 9.45 g±1.38 g, P<0.01). The level of apoptosis of human gastric cell line SGC-7901 was obviously increased in NM-3 treatment group at 1 mg.L -1 for 24 h. NM-3 inducing apoptotic index in NM-3 plus carboplatin group was 3.5 times that of carboplatin control group (TUNEL: 27.98±6.12 % vs 12.94±2.12 %, FACScan: 26.86±5.69 % vs 11.86±1.09 %, P<0.01). Western blot analysis showed that the apoptotic index of human gastric cancer was elevated for 12, 24 and 36 h with an evident time-effect relationship in groups at 100 mg.L -1 . NM-3 enhanced the inhibitive effects and sensitivity of chemotherapy for human gastric cancer in nude mice. These results suggested that NM-3 played a key inhibitive role in the growth of grafted human gastric cancer in nude mice.CONCLUSION: NM-3 can inhibit the growth of human gastric cancer cell line SGC-7901, and enhance the sensitivity of carboplatin on SGC-7901 and induced its apoptosis.

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Different Pattern of Allelic Loss in Epstein-Barr Virus-Positive Gastric Cancer with Emphasis on the p53 Tumor Suppressor Pathway

Cited by 42 publications

References 24 publications

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

Epstein-Barr Virus-Positive Gastric Carcinoma Has a Distinct Protein Expression Profile in Comparison with Epstein-Barr Virus-Negative Carcinoma

Molecule action mechanisms of NM-3 on human gastric cancer SGC-7901 cellsin vivoorin vitro

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