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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defining apoptosis-regulatory cascades of the epithelium is important for understanding carcinogenesis, since cancer cells are considered to arise as a result of the collapse of the cascades. We previously reported that a novel gene GASDERMIN (GSDM) is expressed in the stomach but suppressed in gastric cancer cell lines. Furthermore, in this study, we demonstrated that GSDM is expressed in the mucus-secreting pit cells of the gastric epithelium and frequently silenced in primary gastric cancers. We found that GSDM has a highly apoptotic activity and its expression is regulated by a transcription factor LIM domain only 1 (LMO1) through a sequence to which Runt-related transcription factor 3 (RUNX3) binds, in a GSDM promoter region. We observed coexpression of GSDM with LMO1, RUNX3 and type II transforming growth factor-beta receptor (TGF-betaRII) in the pit cells, and found that TGF-beta upregulates the LMO1- and GSDM-expression in the gastric epithelial cell line and induces apoptosis, which was confirmed by the finding that the apoptosis induction is inhibited by suppression of each LMO1-, RUNX3- and GSDM expression, respectively. The present data suggest that TGF-beta, LMO1, possibly RUNX3, and GSDM form a regulatory pathway for directing the pit cells to apoptosis.
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PMID:GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in TGF-beta-dependent apoptotic signalling. 1747 Dec 40

Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable/fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacter pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NFkappaB signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NFkappaB and TRAF6-MAP3K7-AP-1 signaling cascades in epithelial and immune cells through lipopolysaccharide recognition by TLR2 or TLR4. IL-1beta, IL-6, IL-8, TNFalpha and IFNgamma are elevated in gastric mucosa with Helicobacter pylori infection. IL-6 and TNFalpha induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF, RhoA, JNK, PKC, NFAT, and NLK signaling cascades. WNT-beta-catenin-TCF/LEF signaling induces upregulation of MYC, CCND1, WISP1, FGF20, JAG1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NFkappaB signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC, and NFAT signaling cascades. Helicobacter pylori infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch signaling, while DKK1 and SFRP1 inhibit WNT signaling. Stem cell signaling network, consisting of WNT, Notch, FGF, Hedgehog and BMP signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell signaling network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell signaling molecules could be utilized for the personalized medicine.
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PMID:Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. 1756 83

O-6-methylguanine-DNA methyltransferase (MGMT) repairs inappropriately methylated guanine residues in DNA. MGMT promoter methylation and gene silencing are common events in colorectal cancer, and may or may not co-exist with the CpG island methylator phenotype (CIMP). To date, no study has examined the relationship between MGMT promoter methylation and common MGMT single nucleotide polymorphisms (SNPs), which have been associated with colorectal cancer risk. Utilizing real-time polymerase chain reaction (MethyLight technology), we quantified DNA methylation in MGMT and eight other markers (a CIMP diagnostic panel including CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1 in 182 colorectal cancers collected from two prospective cohorts, the Nurses' Health Study and the Health Professionals Follow-up Study. We genotyped four MGMT germline SNPs in normal DNA and assessed microsatellite instability (MSI), 18q loss of heterozygosity and KRAS and BRAF status in tumors. The presence of a common MGMT promoter SNP (NM_002412.2:c.-56C>T) (rs16906252) was strongly associated with MGMT methylation (multivariate odds ratio 18.0; 95% confidence interval, 6.2-52.1, P < 0.0001). The presence of the c.-56C>T SNP was also associated with loss of MGMT expression in tumors (assessed by immunohistochemistry) (P = 0.009). This promoter SNP was not correlated with KRAS, BRAF, CIMP or MSI status. None of the other three non-promoter SNPs was significantly associated with any molecular changes tested. In conclusion, we have found a strong association between the germline polymorphism (c.-56C>T) of the MGMT promoter and promoter methylation/silencing of MGMT in colorectal cancer. Our data provide compelling evidence for common susceptibility for MGMT promoter CpG island methylation.
Carcinogenesis 2007 Sep
PMID:MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. 1762 91

Recent studies have suggested that Runt-related transcription factor 3 (Runx3) is associated with genesis and progression of gastric carcinoma. A proteomic approach was used to search for Runx3-interacting proteins to elucidate the molecular mechanisms of gastric carcinogenesis. Runx3 bound with myc and flag tags (MEF tags) is expressed in HEK293T cells, and the protein complex formed with Runx3 was purified and identified by mass spectrometry. Ku70 and Ku80, members of the DNA repair protein complex, were identified as Runx3-interacting proteins. Runx3, Ku70, and Ku80 associate in vivo, and in vitro interaction between Runx3 and Ku70 was confirmed via His-tag pull-down assay. The amino acids 241-322 of Runx3, which correspond to the transcriptional activation domain, and the amino acids 1-116 of Ku70 were necessary for binding with each other, and immunocytochemistry under confocal laser microscopy demonstrated that Runx3 and Ku70 localized throughout the nucleus excluding the nucleoli. Furthermore, Runx3 highly activated the transcription of p21, the target gene of Runx3, in Ku70 knockdown cells. These results suggest a possible link between a tumor suppressor function and DNA repair.
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PMID:Runx3 interacts with DNA repair protein Ku70. 1766 72

The RUNX3 gene is regarded as a tumor suppressor gene in many human solid tumors, and its inactivation is believed to be related with solid tumor carcinogenesis. As little information is available about the role of the RUNX3 gene in breast cancer, we investigated the relationship between the RUNX3 gene and breast cancer. We performed reverse transcriptase-polymerases chain reaction (RT-PCR), methylation specific PCR, and bicolor fluorescent in situ hybridization analysis in an effort to reveal related mechanisms. Forty breast tissue samples and 13 cell lines were used in this study. Eighty-five percent of breast cancer tissues showed downregulated RUNX3 gene expression, whereas it was downregulated in only 25% of normal breast tissues by RT-PCR assay. Sixty-seven percent of breast cancer cell lines showed downregulated RUNX3 expression, but the RUNX3 gene was not expressed in two normal breast cell lines. Hypermethylation was observed in 53% of breast cancer tissues and 57% of breast cancer cell lines. Hemizygous deletion was observed in 43% of breast cancer cell lines. Hypermethylation and/or hemizygous deletion was observed in 5 of 7 breast cancer cell lines, and the four of these five examined showed no RUNX3 gene expression. We suggest that various mechanisms, including methylation and hemizygous deletion, could contribute to RUNX3 gene inactivation.
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PMID:Downregulation of the RUNX3 gene by promoter hypermethylation and hemizygous deletion in breast cancer. 1792 51

Estrogen imprinting is used to describe a phenomenon in which early developmental exposure to endocrine disruptors increases breast cancer risk later in adult life. We propose that long-lived, self-regenerating stem and progenitor cells are more susceptible to the exposure injury than terminally differentiated epithelial cells in the breast duct. Mammospheres, containing enriched breast progenitors, were used as an exposure system to simulate this imprinting phenomenon in vitro. Using MeDIP-chip, a methylation microarray screening method, we found that 0.5% (120 loci) of human CpG islands were hypermethylated in epithelial cells derived from estrogen-exposed progenitors compared with the non-estrogen-exposed control cells. This epigenetic event may lead to progressive silencing of tumor suppressor genes, including RUNX3, in these epithelial cells, which also occurred in primary breast tumors. Furthermore, normal tissue in close proximity to the tumor site also displayed RUNX3 hypermethylation, suggesting that this aberrant event occurs in early breast carcinogenesis. The high prevalence of estrogen-induced epigenetic changes in primary tumors and the surrounding histologically normal tissues provides the first empirical link between estrogen injury of breast stem/progenitor cells and carcinogenesis. This finding also offers a mechanistic explanation as to why a tumor suppressor gene, such as RUNX3, can be heritably silenced by epigenetic mechanisms in breast cancer.
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PMID:Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. 1833 59

We have reported that a lack of RUNX3 function is causally associated with gastric carcinogenesis. We have also presented evidence that loss of Runx3 may be related to the genesis of intestinal metaplasia because expression of RUNX3 is reduced in some intestinal metaplasias, and some Runx3(-/-)p53(-/-) gastric epithelial cells differentiate into intestinal type cells in vivo. Recently several reports have indicated that blood cells play important roles in the gastric carcinogenesis. In the present study, we therefore examined whether Runx3(-/-)p53(-/-) gastric epithelial cells differentiate autonomously into intestinal type cells, or whether the presence of other cells is necessary for the differentiation in vitro. When Runx3(-/-)p53(-/-) gastric epithelial cells were cultured with collagen gels, they did not exhibit any morphogenesis and differentiated poorly. When cultured with fetal mouse gastric mesenchymes, the cells formed glandular structures and differentiated into surface mucous cells, but differentiation of intestinal type cells was never observed. When cultured with Matrigel, the cells formed glandular structures, and some cells differentiated into intestinal type cells in vitro. Reverse transcription-polymerase chain reaction analysis showed that the cells expressed stomach-specific genes, and their levels decreased gradually during the culture. The cells expressed some intestine-specific genes weakly at the start of culture, and their levels were increased with time in culture. We therefore conclude that Runx3(-/-)p53(-/-) gastric epithelial cells differentiate into intestinal type cells in combination with Matrigel in the absence of other cell types. Extracellular matrix, not blood cells, may play a role in the genesis of intestinal metaplasia.
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PMID:In vitro differentiation of Runx3-/- p53-/- gastric epithelial cells into intestinal type cells. 1837 19

Transforming growth factor-beta (TGF-beta) is a multifunctional growth factor that plays important roles in many biological processes, whereas RUNX3 is a target of TGF-beta-mediated tumor suppressor pathway. In humans, RUNX3 inactivation may lead to the cancer development, including bladder cancer. To determine whether the RUNX3 polymorphisms are associated with risk of bladder cancer, we conducted a case-control study of 368 bladder cancer patients and 368 cancer-free controls to assess the associations between the RUNX3 tagging single-nucleotide polymorphisms (tSNPs) and bladder cancer risk. In the single-locus analysis, we found a significantly increased risk of bladder cancer associated with the SNP7 rs760805 AA genotype (adjusted odds ratio = 1.97, 95% confidence interval = 1.44-2.69), compared with the AT/TT genotype. Haplotype-based association analysis revealed that the increased risk of bladder cancer was significantly associated with two haplotypes TATCCCAAAA (2.37, 1.16-4.83) and AGCTTGAGAG (2.70, 1.08-6.72) that included the rs760805 A allele. Multifactor dimensionality reduction (MDR) analysis identified a significant more than multiplicative interaction between the SNP7 rs760805 AA and smoking and an additive interaction between the SNP3 rs11249206 TT and smoking on bladder cancer risk. The SNP3 rs11249206, SNP5 rs1395621, SNP7 rs760805, SNP8 rs2236852 and the trichotomized cumulative smoking were the five factors best predicted by the MDR models. When the variables were combined and dichotomized and fitted into the MDR model, the subjects carrying the combined risk stratum had a significantly increased risk for bladder cancer (6.37, 4.57-8.87, P = 7.03 x 10(-28)). These results suggested that the genetic variants in RUNX3 may modulate the risk of bladder cancer.
Carcinogenesis 2008 Oct
PMID:Genetic variants in RUNX3 and risk of bladder cancer: a haplotype-based analysis. 1868 27

RUNX3 is a novel tumor suppressor in gastric carcinogenesis and an important factor for differentiation of chief cells in the normal gastric fundic mucosa. In this study, we confirmed RUNX3 immunolocalization in the fundic gland (bottom part) but minimum in surface mucous cell epithelium (top part) in the isolated gland from fundic mucosa. We also analyzed RUNX3 expression by immunohistochemistry in 102 gastric cancers and made a histological assessment of the expression of differentiation markers to evaluate interrelations. Among them, 45 and 57 cases were judged to be RUNX3 positive and negative, respectively, and 33 and 69 cases were pepsinogen I positive and negative, with no link to histological types. RUNX3 expression was significantly associated with that of pepsinogen I (P<0.001), but not mucins, including MUC5AC and MUC6, or the parietal or intestinal phenotypes. In conclusion, the present study showed, for the first time to our knowledge, a relation between RUNX3 and pepsinogen I expression in human gastric cancers. RUNX3 is strongly associated with chief cell phenotypic expression in human gastric cancers, as well as in normal gastric mucosa, and could be considered to play an important role in maintaining the chief cell phenotype.
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PMID:RUNX3 expression correlates with chief cell differentiation in human gastric cancers. 1901 42

A major goal of molecular biology is to elucidate the mechanisms underlying cancer development and progression in order to achieve early detection, better diagnosis and staging and novel preventive and therapeutic strategies. We feel that an understanding of Runt-related transcription factor 3 (RUNX3)-regulated biological pathways will directly impact our knowledge of these areas of human carcinogenesis. The RUNX3 transcription factor is a downstream effector of the transforming growth factor-beta (TGF-beta) signaling pathway, and has a critical role in the regulation of cell proliferation and cell death by apoptosis, and in angiogenesis, cell adhesion and invasion. We previously identified RUNX3 as a major gastric tumor suppressor by establishing a causal relationship between loss of function and gastric carcinogenesis. More recently, we showed that RUNX3 functions as a bona fide initiator of colonic carcinogenesis by linking the Wnt oncogenic and TGF-beta tumor suppressive pathways. Apart from gastric and colorectal cancers, a multitude of epithelial cancers exhibit inactivation of RUNX3, thereby making it a putative tumor suppressor in human neoplasia. This review highlights our current understanding of the molecular mechanisms of RUNX3 inactivation in the context of cancer development and progression.
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PMID:Molecular pathology of RUNX3 in human carcinogenesis. 1968 50


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