Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04155 (pS2)
 1,234 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the function of the pS2 trefoil protein, which is normally expressed in the gastric mucosa, the mouse pS2 (mpS2) gene was inactivated. The antral and pyloric gastric mucosa of mpS2-null mice was dysfunctional and exhibited severe hyperplasia and dysplasia. All homozygous mutant mice developed antropyloric adenoma, and 30 percent developed multifocal intraepithelial or intramucosal carcinomas. The small intestine was characterized by enlarged villi and an abnormal infiltrate of lymphoid cells. These results indicate that mpS2 is essential for normal differentiation of the antral and pyloric gastric mucosa and may function as a gastric-specific tumor suppressor gene.
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PMID:Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein. 892 80

Serrated adenoma of the colorectum was a newly proposed entity in 1990, characterized by epithelial neoplasia combining the architectural features of a hyperplastic (metaplastic) polyp with the cytological features of an adenoma. Its histogenesis and natural history still remain unclear. Forty-six serrated adenomas were obtained from 46 patients. The clinicopathological features were summarized. Paraffin-embedded blocks from 34 serrated adenomas were available for immunohistochemical studies using pS2, human gastric mucin, and p53 protein. Eighteen hyperplastic (metaplastic) polyps, 16 tubular adenomas, and 12 early-stage adenocarcinomas were randomly selected as control groups for immunohistochemical analysis. The patients' ages ranged from 32 to 86 (average 61.4) years. Males were more frequently affected than females. Serrated adenomas were predominantly present in the left-side of the colon and in the rectum (72 per cent). Their sizes ranged from 3 to 26 mm (average 9. 2mm). Six lesions (13 per cent) contained foci of high-grade dysplasia. These adenomas were significantly larger (12.7 mm) than those containing no high-grade dysplasia (8.6mm). pS2 and human gastric mucin were expressed significantly more frequently in both hyperplastic (metaplastic) polyps and serrated adenomas than in tubular adenomas or adenocarcinomas. p53-positive cells were present in 18 of the 29 pure serrated adenomas (62 per cent) and in one of the five areas of low-grade dysplasia in serrated adenomas with high-grade dysplasia (20 per cent), most of which revealed a sporadic distribution. Only five of the 29 serated adenomas with no high-grade dysplasia (17 per cent) were regarded as demonstrating p53 overexpression. On the other hand, three of the five areas of high-grade dysplasia in serrated adenomas (60 per cent) revealed diffuse positivity (3+) for p53 protein. The serrated adenoma, which possibly shows gastric differentiation, is considered to be an independent histological entity among the various phenotypes of colorectal adenomas. Serrated adenoma would seem to be a precursor of carcinoma, its potential for malignant transformation being similar to that of the traditional tubular adenoma. It would also seem that p53 is involved in the serrated adenoma-carcinoma sequence.
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PMID:'Serrated' adenoma of the colorectum, with reference to its gastric differentiation and its malignant potential. 1039 12

A 70-year-old woman underwent right hemicolectomy and six carcinomas were recognized in the resected colon. These carcinomas were considered to be of a cell lineage common to serrated adenoma (SA) and hyperplastic (metaplastic) polyp (H/MP), because of the occurrence of multiple SAs and H/MPs around the carcinomas, as well as the co-existence of SA and H/MP areas within the carcinomas. These carcinomas had the following common histological and immunohistochemical features: a serrated structure resembling SA; a lace-like structure; infiltrative growth within the muscularis propria, with dedifferentiation at the invasive front; and immunohistochemical expression of pS2 and human gastric mucin. Based on these features, a new subtype of carcinoma is proposed, with a cell lineage common to SA and H/MP. It would also seem that p53 is involved in the serrated adenoma-carcinoma sequence.
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PMID:Multiple 'serrated adenocarcinomas' of the colon with a cell lineage common to metaplastic polyp and serrated adenoma. Case report of a new subtype of colonic adenocarcinoma with gastric differentiation. 1069 93

Trefoil factors (TFFs) are protease-resistant peptides that promote epithelial cell migration and mucosal restitution during inflammatory conditions and wound healing in the gastrointestinal tract. To date, the molecular mechanism of TFFs action and their possible role in tumor progression are unclear. In the present study, we observed that premalignant human colonic PC/AA/C1 and canine kidney MDCK epithelial cells are not competent to invade collagen gels in response to exogenously added TFFs (pS2, spasmolytic polypeptide, and intestinal trefoil factor). In contrast, activated src and RhoA exert permissive induction of invasion by the TFFs that produce similar parallel dose-response curves in src-transformed MDCKts.src and PCmsrc cells (EC50=20-40 nM). Cell scattering is also induced by TFFs in MDCKts.src cells. Stable expression of the pS2 cDNA promotes constitutive invasiveness in MDCKts.src-pS2 cells and human colonic HCT8/S11-pS2 cells established from a sporadic tumor. Furthermore, we found that TFF-mediated cellular invasion is dependent of several signaling pathways implicated in cell transformation and survival, including phosphoinositide PI3'-kinase, phospholipase C, protein kinase C, and the rapamycin target TOR. Constitutive and intense expression of pS2 was revealed by Western blot analyses and immunohistochemistry in human colorectal tumors and their adjacent control mucosa during the neoplastic progression, from the adenoma to the liver metastases. Our studies indicated that TFFs can be involved in cell scattering and tumor invasion via autocrine loops and may serve as potential targets in the control of colon cancer progression.
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PMID:Induction of scattering and cellular invasion by trefoil peptides in src- and RhoA-transformed kidney and colonic epithelial cells. 1115 51

Expression of cyclooxygenase-2 (Cox-2) is elevated in gastric adenocarcinomas and precursor lesions leading to this disease. Mice deficient for trefoil factor 1 (TFF1) develop a pyloric adenoma with full penetrance. Because inhibition of Cox-2 suppresses tumor growth in several animal models, we studied expression of Cox-2 and effect of a selective Cox-2 inhibitor celecoxib in gastrointestinal tissues of the TFF1-deficient mice. Cox-2 mRNA and protein were strongly expressed in the pyloric adenomas of the TFF1(-/-) mice as detected by in situ hybridization and immunohistochemistry. Nonneoplastic gastrointestinal tissues of wild-type or TFF1(-/-) mice expressed low or nondetectable levels of Cox-2. Celecoxib (1600 ppm p.o. for 3 months) caused ulceration and inflammation of the adenoma in all treated TFF1(-/-) mice (n = 7). This effect of the drug was adenoma specific, because no histological alterations were observed in the non-neoplastic gastric or intestinal tissues in the TFF1(-/-) or wild-type mice receiving the drug treatment. All untreated TFF1(-/-) mice had an adenoma (n = 7), but none demonstrated the combination of ulceration and inflammation. Our data show that Cox-2 is expressed in gastric adenomas of the TFF1(-/-) mice and suggest that inhibition of Cox-2 disturbs the integrity of the adenoma by promoting ulceration and inflammation. These findings support the effort to initiate clinical studies to investigate the effect of Cox-2 inhibitors as a chemotherapeutic modality for dysplasias of the stomach.
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PMID:Cyclooxygenase-2 expression and effect of celecoxib in gastric adenomas of trefoil factor 1-deficient mice. 1281 Jun 22

Multiple genetic and epigenetic alterations in oncogenes, tumour-suppressor genes, cell-cycle regulators, cell adhesion molecules, DNA repair genes and genetic instability as well as telomerase activation are implicated in the multistep process of human stomach carcinogenesis. However, particular combinations of these alterations differ in the two histological types of gastric cancer, indicating that well-differentiated or intestinal-type and poorly differentiated or diffuse-type carcinomas have distinct carcinogenetic pathways. In the multistep process of well-differentiated-type carcinogenesis, the genetic pathway can be divided into three subpathways: an intestinal metaplasia-->adenoma-->carcinoma sequence, an intestinal metaplasia-->carcinoma sequence and de novo. In the multistep process of well-differentiated-type or intestinal-type gastric carcinogenesis, infection with Helicobacter pylori may be a strong trigger for hyperplasia of hTERT-positive 'stem cells' in intestinal metaplasia. Genetic instability and hyperplasia of hTERT-positive stem cells precede replication error at the D1S191 locus, DNA hypermethylation at the D17S5 locus, pS2 loss, RARbeta loss, CD44 abnormal transcripts and p53 mutation, all of which accumulate in at least 30% of incomplete intestinal metaplasias. All of these epigenetic and genetic alterations are common events in intestinal-type gastric cancer. An adenoma-->carcinoma sequence is found in about 20% of gastric adenomas with APC mutations. In addition to these events, p53 mutation and loss of heterozygosity (LOH), reduced p27 expression, cyclin E expression and the presence of c-met 6.0-kb transcripts allow malignant transformation from the above precancerous lesions to intestinal-type gastric cancer. DCC loss, APC mutations, 1q LOH, p27 loss, reduced tumour growth factor (TGF)-beta type I receptor expression, reduced nm23 expression and c-erbB gene amplification are frequently associated with an advanced stage of intestinal-type gastric cancer. The de-novo pathway for carcinogenesis of well-differentiated gastric cancer involves LOH and abnormal expression of the p73 gene that is responsible for the development of foveolar-type gastric cancers with pS2 expression. On the other hand, LOH at chromosome 17p, mutation or LOH of p53 and mutation or loss of E-cadherin are preferentially involved in the development of poorly differentiated gastric cancers. In addition to these changes, gene amplification of K-sam, and c-met and p27 loss as well as reduced nm23 obviously confer progression, metastasis and diffusely productive fibrosis. Mixed gastric carcinomas composed of well-differentiated and poorly differentiated components exhibit some but not all of the molecular events described so far for each of the two types of gastric cancer. Besides these genetic and epigenetic events, well-differentiated and poorly differentiated gastric cancers also organize different patterns of interplay between cancer cells and stromal cells through the growth factor/cytokine receptor system, which plays an important role in cell growth, apoptosis, morphogenesis, angiogenesis, progression and metastasis. Meta-analysis of epidemiological studies and animal models show that both intestinal and diffuse types of gastric cancer are equally associated with H. pylori infection. However, H. pylori infection may play a role only in the initial steps of gastric carcinogenesis. Differences in H. pylori strain, patient age, exogenous or endogenous carcinogens and genetic factors such as DNA polymorphism and genetic instability may be implicated in two distinct major genetic pathways for gastric carcinogenesis.
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PMID:Genetic pathways of two types of gastric cancer. 1505 5

TFF1 is overexpressed in inflammatory diseases and human cancers of the digestive and urogenital systems. To examine the transforming potential of TFF1 in human colon epithelial cells, premalignant PC/AA/C1 adenoma cells (PC) derived from a patient with familial adenomatous polyposis (FAP) were transformed by the TFF1 cDNA and used as a model of the adenoma-carcinoma transition. Constitutive expression of TFF1 increased anchorage-independent cell growth in soft agar, and induced or potentiated the growth of colon PC-TFF1 and kidney MDCKts.src-TFF1 tumor xenografts in athymic mice. This resulted in reduction of thapsigargin-induced apoptosis and promotion of collagen type I invasion through several oncogenic pathways. Using the differential display approach to identify TFF1 target genes, we found that the dual specific phosphatases Cdc25A and B implicated in cell cycle transitions are strongly upregulated under active forms in both PC-TFF1 and HCT8/S11-TFF1 colon cancer cells. Accordingly, TFF1 expression is absent in normal human colon crypts but is induced in correlation with Cdc25a and b transcript levels and tumor grade in familial and sporadic colon adenomas and carcinomas. We propose that TFF1 and Cdc25A-B cooperate with other dominant oncogenic pathways to induce the adenoma and adenocarcinoma transitions. Agents that target TFF1/Cdc25 signaling pathways may be useful for treating patients with TFF1-positive solid tumors.
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PMID:Induction of the adenoma-carcinoma progression and Cdc25A-B phosphatases by the trefoil factor TFF1 in human colon epithelial cells. 1671 41

The serrated polyp-neoplasia pathway is a novel concept that has been demonstrated to differ from the conventional adenoma-carcinoma pathway. To characterize the phenotypic patterns of differentiation in colorectal serrated polyps, we examined the immunohistochemical expression profile of gastric (MUC5AC, TFF1, MUC6, GlcNAcalpha1 --> 4Gal --> R, and PDX1) and intestinal (MUC2, TFF3, and CDX2) epithelial markers in 15 hyperplastic polyps (HPs), 29 sessile serrated adenomas (SSAs),12 traditional serrated adenomas (TSAs), and 16 conventional adenomas (CAs). MUC5AC and TFF1 were upregulated in the HPs, SSAs, and TSAs. MUC6 was expressed in the HPs and SSAs. GlcNAcalpha1 --> 4Gal --> R was expressed only in the SSAs. Although MUC2 expression was preserved, TFF3 was downregulated in the HPs, SSAs, and TSAs. PDX1 was upregulated in the HPs, SSAs, and TSAs. On the other hand, CDX2 was downregulated in the HPs and SSAs. The colorectal serrated polyps showed higher expression of gastric makers than CAs. The HPs and SSAs showed gastric and intestinal mixed phenotype expression with gastric pyloric organoid differentiation and almost identical, but different from the TSAs, marker profile. PDX1 up-regulation and CDX2 down-regulation could be important for the induction of a gastric pyloric pattern of cell differentiation in colorectal serrated polyps.
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PMID:Hyperplastic polyps and sessile serrated 'adenomas' of the colon and rectum display gastric pyloric differentiation. 1785 79

A subset of gastric carcinomas shows histologic evidence of a multistep process, progressing from gastric adenoma to gastric carcinoma. We examined gene expression changes during the gastric adenoma-carcinoma sequence in 26 snap-frozen samples (normal mucosa, adenoma, and carcinoma samples from eight patients and two additional carcinomas) by oligonucleotide microarray. Unsupervised hierarchical clustering analysis demonstrated differential gene expression between gastric normal mucosa, adenomas and carcinomas. We identified 319 and 422 genes differentially regulated in adenoma and carcinoma, respectively, relative to normal mucosa, using a combination of Welch's t-test and fold-change analysis. Applying a combination of robust multi-category support vector machines to the data, reveal that 39 and 21 genes were gradually up- and down-regulated, respectively, in succession in normal mucosa, adenoma, and carcinoma samples. We validated gene expression levels of four genes: hydroxyprostaglandin dehydrogenase 15 (HPGD), follistatin-like 1, trefoil factor 1 (TTF1) and trefoil factor 2 (TFF2) by RT-PCR and found direct correlation with microarray results. The expressions of the TFF2 and HPGD genes were further evaluated by immunohistochemistry in 103 adenomas and 70 carcinomas; expression of both proteins was decreased in these tissues. The progressive alteration in gene expression in the transition from normal mucosa to carcinoma suggests that these changes may play critical roles in gastric carcinogenesis.
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PMID:Gene expression changes in patient-matched gastric normal mucosa, adenomas, and carcinomas. 2118 29

Cyclooxygenase-2 (Cox-2) expression is a marker of reduced survival in gastric cancer patients, and inhibition of Cox-2 suppresses gastrointestinal carcinogenesis in experimental animal models. To investigate the role of Cox-2 in gastric carcinogenesis in vivo, we utilized trefoil factor 1 (Tff1) deficient mice, which model the neoplastic process of the stomach by developing gastric adenomas with full penetrance. These tumors express Cox-2 protein and mRNA, and we have now investigated the effects of genetic deletion of the mouse Cox-2 gene [also known as prostaglandin-endoperoxide synthase 2 (Ptgs2)] and a Cox-2 selective drug celecoxib. Our results show that genetic deletion of Cox-2 in the Tff1 deleted background resulted in reduced adenoma size and ulceration with a chronic inflammatory reaction at the site of the adenoma. To characterize the effect of Cox-2 inhibition in more detail, mice that had already developed an adenoma were fed with celecoxib for 8-14 weeks, which resulted in disruption of the adenoma that ranged from superficial erosion to deep ulcerated destruction accompanied with chronic inflammation. Importantly, mice fed with celecoxib for 16 weeks, followed by control food for 9 weeks, redeveloped a complete adenoma with no detectable inflammatory process. Finally, we determined the identity of the Cox-2 expressing cells and found them to be fibroblasts. Our results show that inhibition of Cox-2 is sufficient to reversibly disrupt gastric adenomas in mice.
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PMID:Inhibition of cyclooxygenase-2 causes regression of gastric adenomas in trefoil factor 1 deficient mice. 2203 55


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