Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Runx3/Pebp2alphaC null mouse gastric mucosa exhibits hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to growth-inhibitory and apoptosis-inducing action of TGF-beta, indicating that Runx3 is a major growth regulator of gastric epithelial cells. Between 45% and 60% of human gastric cancer cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of human gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression, and a mutation (R122C) occurring within the conserved Runt domain abolished the tumor-suppressive effect of RUNX3, suggesting that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer.
 ...
PMID:Causal relationship between the loss of RUNX3 expression and gastric cancer. 1247 50

We reported recently that the silencing of RUNX3 is causally related to gastric cancer in humans. Here we report that in three of four cell lines derived from N-methyl-N-nitrosourea-induced mouse glandular stomach carcinomas, Runx3 is silenced due to hypermethylation of CpG islands in the promoter region, as we also observed for human gastric cancer cells. Although two of the sites we tested in the promoter of the fourth line were not methylated, in all four cases the silencing of Runx3 could be reversed by treatment of the cells with 5'-azacytidine and trichostatin A. Interestingly, the exogenous expression of RUNX3 in cell lines that do not express the endogenous gene caused an inhibition of growth in soft agar, suggesting that anchorage-independent growth could be used as an assay of RUNX3 activity in vitro. These observations suggest that the mouse system described here may be useful as a model for the study of human gastric carcinogenesis.
 ...
PMID:Inhibition of growth of mouse gastric cancer cells by Runx3, a novel tumor suppressor. 1244 99

The Runt domain transcription factors, RUNX1, RUNX2 and RUNX3, are integral components of signaling cascades mediated by both TGF-beta and bone morphogenetic proteins (BMPs) in several important biological systems. RUNX2 functions synergistically with Smad1 and Smad5 to regulate bone-specific genes when BMP induces osteogenesis. RUNX3, which has been mapped to locus 1p36, is a major tumor suppressor of gastric cancer and appears to be an important component of the TGF-beta-induced tumor suppressor pathway. A possible relationship between the TGF-beta-induced tumor-suppressor pathway and a postulated tumor suppressor gene on 1p36 must be examined.
 ...
PMID:RUNX transcription factors as key targets of TGF-beta superfamily signaling. 1257 34

Silencing of tumor suppressor and tumor-related genes by hypermethylation at promoter CpG islands is frequently found in human tumors, including gastric cancer. Promoter methylation is not restricted to cancer cells, and is also present in non-neoplastic cells as an age-related tissue-specific phenomenon. To clarify the physiological consequence of DAP-kinase and RUNX3 age-related methylation in gastric epithelia, we investigated the promoter methylation status of these genes in both neoplastic and non-neoplastic gastric epithelia obtained at autopsy and surgery, as well as in 10 gastric cancer cell lines. Methylation of DAP-kinase and RUNX3 was detected in 10% (1/10) and 70% (7/10) of the cell lines, respectively, and was almost concordant with their expression status. Among autopsy samples, methylation of these genes was not seen in non-neoplastic gastric epithelia from persons who were aged 22 years and below (0%; 0/4). DAP-kinase was methylated in 87% (13/15) of non-neoplastic gastric epithelia of persons who were aged 45 years or older, while RUNX3 methylation in non-neoplastic gastric epithelia was restricted to individuals who were aged 77 years or older. Among samples obtained from patients with stomach cancer, methylation was observed in both the neoplastic and the corresponding non-neoplastic gastric epithelia; 43% (40/93) and 73% (68/93) for DAP-kinase, and 45% (42/93) and 8% (7/93) for RUNX3, respectively. Frequencies of DAP-kinase and RUNX3 methylation differed significantly in non-neoplastic gastric epithelia (P < 0.01), although those in gastric cancers were almost the same. RUNX3 methylation is mostly cancer-specific, except for very old individuals, and therefore may be a possible molecular diagnostic marker and malignancy predictor.
 ...
PMID:Promoter methylation status of DAP-kinase and RUNX3 genes in neoplastic and non-neoplastic gastric epithelia. 1282 5

Topics discussed here include PTEN mutations and colonic polyps; WNT signaling, APC, beta-catenin, and gastrointestinal neoplasms; mismatch-repair genes (MLH1, MSH2, PMS1, MSH6) and hereditary nonpolyposis colorectal cancer; MYH mutations and autosomal recessive colorectal tumors; STK11 mutations and Peutz-Jeghers syndrome; TGFbeta and gastrointestinal cancer; BMPR1A mutations and juvenile polyposis; FGF/FGFR alterations in gastrointestinal neoplasms; PTCH mutations and gastrointestinal neoplasms; RUNX3 expression and gastric cancer; role of mucins in gastric carcinogenesis; KIT, PDGFRalpha, and gastrointestinal stromal tumors; intestinal neurofibromatosis; and gastrointestinal tumors in other disorders.
 ...
PMID:Molecular dimensions of gastrointestinal tumors: some thoughts for digestion. 1451 68

Gastric cancer continues to be a major public health problem and is the second most common cause of cancer-related deaths in the world. These statistics led the American Society of Clinical Oncology (ASCO) International Affairs Committee to choose gastric cancer as the topic for the International Symposium held at the 2003 ASCO Annual Meeting. Dr Yoshiaki Ito will discuss the role of RUNX3 in the genesis and progression of human gastric cancer. Dr Pelayo Correa will present a compelling argument on the use of Helicobacter pylori therapy and antioxidants in selected high-risk population as chemoprevention strategies for gastric cancer. The controversy regarding the role of extended lymph node dissection for gastric cancer will be discussed by Dr Cornelis J.H. Van De Velde and Dr Mitsuru Sasako. Dr Van De Velde will present the European surgical approach to gastric cancer, and Dr Sasako will review the Japanese experience. The issues of whether certain patients benefit from more aggressive surgical dissection and the potential risks compared with benefits will also be discussed. Dr John Macdonald will discuss the role of adjuvant chemotherapy and adjuvant chemoradiotherapy in resected gastric cancer, as well as the role of chemotherapy in metastatic gastric cancer.
 ...
PMID:Therapeutic strategies in gastric cancer. 1464 6

A number of tumor suppressor and tumor-related genes exhibit promoter hypermethylation with resulting gene silencing in human cancers. In addition, several gene promoters have also been shown to become hypermethylated in non-neoplastic cells during aging. To assess the physiological consequence and clinical significance of gene promoter methylation in gastric epithelia, our laboratory has studied the methylation status of tumor suppressor and tumor-related genes, including APC, DAP-kinase, DCC, E-cadherin, GSTP1, hMLH1, p16, PTEN, RASSF1A, RUNX3 and TSLC1, in neoplastic and non-neoplastic gastric epithelia. The tumor suppressor and tumor-related genes, except APC, were generally unmethylated in non-neoplastic gastric epithelia obtained from younger individuals. The frequencies of methylation increased with age to varying degrees in various genes, although GSTP1 and PTEN methylation was completely absent in both neoplastic and non-neoplastic gastric epithelia. The methylation frequencies in each gene were found to be comparable in neoplastic and non-neoplastic gastric epithelia, except the methylation of RUNX3 and TSLC1, which was mostly cancer-specific (P<0.01). When methylation frequencies were compared between non-neoplastic gastric epithelia from cancer-bearing and non-cancer-bearing stomachs, hMLH1 and p16 methylation was more frequent in those from cancer-bearing stomachs (P<0.01). Promoter methylation in tumor suppressor and tumor-related genes initially occurs in non-neoplastic gastric epithelia, increases with age, and ultimately silences gene function to constitute a field-defect that may predispose tissues to gastric cancer evolution. In clinical applications RUNX3 and TSLC1 methylation may be utilized as molecular diagnostic markers, and hMLH1 and p16 methylation as predictors of malignancy in the stomach.
 ...
PMID:Promoter methylation status of tumor suppressor and tumor-related genes in neoplastic and non-neoplastic gastric epithelia. 1470 90

Accumulating evidence has identified a mechanism potentially responsible for the inactivation of tumor suppressor genes, namely transcriptional silencing by aberrant methylation of CpG islands. A previous study has shown the loss of RUNX3 expression, due to aberrant methylation of its CpG island, in gastric cancer cell lines, suggesting that RUNX3 is a target for epigenetic gene silencing in gastric carcinogenesis. However, there are limited data on the methylation status of RUNX3 in the neoplastic and non-neoplastic tissues in various types of human cancers, including gastric cancer. Here, we report that 60% of gastric cancer cell lines and 64% of primary gastric carcinomas (n=75) were methylated at the RUNX3 CpG island. RUNX3 methylation was also detected in hepatocellular carcinomas (73%, n=48), larynx cancers (62%, n=37), lung cancers (46%, n=24), breast cancers (25%, n=25), prostate cancers (23%, n=44), endometrial cancers (12.5%, n=24), colon cancers (4.9%, n=61) and uterine cervical cancers (2.5%, n=40), showing that RUNX3 methylation is not restricted to gastric cancer. Interestingly, the RUNX3 methylation was especially frequent in tumors from tissues of a foregut derivative, that is, the stomach, liver, larynx and lung. Next, the methylation status of RUNX3 in various non-neoplastic tissues was examined, including the premalignant lesions of gastric carcinomas. The RUNX3 methylation was found in 8.1% of chronic gastritis (n=99), 28.1% of intestinal metaplasia (n=32), 27.3% of gastric adenomas (n=77) and 64% of gastric carcinomas (n=75), but not in chronic hepatitis B, normal prostate and colon mucosa, even though in cases of chronic hepatitis, the methylation frequency of its neoplastic tissues was very high. In conclusion, RUNX3 methylation is frequently found in human cancers, including gastric cancer, and is mostly cancer specific, with the exception of the stomach, and thus, might be useful as a potential diagnostic biomarker of cancer.
 ...
PMID:Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. 1496 23

The Runt domain transcription factors (RUNXs) play essential roles in normal development and neoplasias. Genetic analyses of animals and humans have revealed the involvement of RUNX1 in hematopoiesis and leukemia, RUNX2 in osteogenesis and cleidocranial dysplasia, and RUNX3 in the development of T-cells and dorsal root ganglion neurons and in the genesis of gastric cancer. Here we report that RUNX3 is a target of the acetyltransferase activity of p300. The p300-dependent acetylation of three lysine residues protects RUNX3 from ubiquitin ligase Smurf-mediated degradation. The extent of the acetylation is up-regulated by the transforming growth factor-beta signaling pathway and down-regulated by histone deacetylase activities. Our findings demonstrate that the level of RUNX3 protein is controlled by the competitive acetylation and deacetylation of the three lysine residues, revealing a new mechanism for the posttranslational regulation of RUNX3 expression.
 ...
PMID:Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. 1513 60

Runt-related (RUNX) gene family is composed of three members, RUNX1/AML1, RUNX2 and RUNX3, and encodes the DNA-binding (alpha) subunits of the Runt domain transcription factor polyomavirus enhancer-binding protein 2 (PEBP2)/core-binding factor (CBF), which is a heterodimeric transcription factor. RUNX1 is most frequently involved in human acute leukemia. RUNX2 shows oncogenic potential in mouse experimental system. RUNX3 is a strong candidate as a gastric cancer tumor suppressor. The beta subunit gene of PEBP2/CBF is also frequently involved in chromosome rearrangements associated with human leukemia. In this Overview, I will summarize how this growing field has been formed and what are the challenging new frontiers for better understanding of the oncogenic potential of this gene family.
 ...
PMID:Oncogenic potential of the RUNX gene family: 'overview'. 1515 73


1 2 3 4 5 6 7 8 9 10 Next >>