Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel phosphorylation-specific antibody (alphapbeta-catenin) was generated against a peptide corresponding to amino acids 33-45 of human beta-catenin, which contained phosphorylated serines at positions 33 and 37. This antibody is specific to phosphorylated beta-catenin and reacts neither with the non-phosphorylated protein nor with phosphorylated or non-phosphorylated plakoglobin. It weakly interacts with S33Y beta-catenin but not with the S37A mutant. pbeta-catenin is hardly detectable in normal cultured cells and accumulates (up to 55% of total beta-catenin) upon overexpression of the protein or after blocking its degradation by the proteasome. Inhibition of both GSK-3beta and the proteasome resulted in a rapid (t1/2=10 minutes) and reversible reduction in pbeta-catenin levels, suggesting that the protein can undergo dephosphorylation in live cells, at a rate comparable to its phosphorylation by GSK-3beta. pbeta-catenin interacts with LEF-1, but fails to form a ternary complex with DNA, suggesting that it is transcriptionally inactive. Immunofluorescence microscopy indicated that pbeta-catenin accumulates in the nuclei of MDCK and BCAP cells when overexpressed and is transiently associated with adherens junctions shortly after their formation. pbeta-catenin only weakly interacts with co-transfected N-cadherin, although it forms a complex with the ubiquitin ligase component beta-TrCP. SW480 colon cancer cells that express a truncated APC, at position 1338, contain high levels of pbeta-catenin, whereas HT29 cells, expressing APC truncated at position 1555, accumulate non-phosphorylated beta-catenin, suggesting that the 1338-1555 amino acid region of APC is involved in the differential regulation of the dephosphorylation and degradation of pbeta-catenin.
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PMID:Regulation of S33/S37 phosphorylated beta-catenin in normal and transformed cells. 1207 67

Although dehydroepiandrosterone (DHEA) is recognized as one of the major adrenal androgens, its precise physiological role in the human endocrine system remains to be elucidated. In particular, the effect of DHEA on carcinogenesis has not been fully characterized. We undertook this study to determine whether DHEA has a chemopreventative effect on the precursors of colon cancer in a murine model of azoxymethane (AOM)-induced aberrant crypt foci (ACF). The number of ACF was significantly decreased in mice treated with 0.4% (p < 0.001) and 0.8% DHEA (p < 0.001), but there were no significant differences between DHEA-treated and control mice in terms of the ACF size, 3-catenin expression or level of dysplasia. This is the first study of colon cancer carcinogenesis demonstrating that DHEA treatment can decrease the number of ACF without apparently modifying their malignant potential. These data strongly suggest that DHEA might be a potential chemopreventative agent against human colon cancer.
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PMID:Chemoprevention of precursors to colon cancer by dehydroepiandrosterone (DHEA). 1226 89

In subclones of the human colon cancer LoVo cell line, there is a reproducible spontaneous transition from an epithelioid (E) to a round (R) morphotype. The E to R transition is associated with increased cell growth, absence of E-cadherin-dependent compaction in a slow aggregation assay, loss of contact inhibition of motility and directional migration in a wound filling motility assay. Furthermore, none of the E subclones from LoVo was invasive into chick heart fragments. This is in contrast to the R subclones that were either nonadherent or adherent and invasive. Macroarray analysis demonstrated transcriptional downregulation of plakoglobin in R type LoVo cells and this was confirmed at the level of the mRNA by quantitative RT-PCR. Western blotting showed lower expression of all components of the E-cadherin/catenin complex in R subclones. Interestingly, treatment of R subclones with the demethylating agent 5-aza-2'-deoxycytidine resulted in restoration of the E morphotype, higher expression of E-cadherin, but not plakoglobin mRNA, and higher expression of E-cadherin and plakoglobin at the protein level.
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PMID:Functional and molecular characterization of the epithelioid to round transition in human colorectal cancer LoVo cells. 1456 48

Beta-catenin and cyclin D1 have attracted considerable attention due to their proto-oncogenic roles in human cancer. The finding of cyclin D1 as a direct target gene of beta-catenin in colon cancer cells led to the assumption that cyclin D1 upregulation is pivotal to beta-catenin's oncogenicity. Our recent paper shows that this is not the case; cyclin D1 dampens the oncogenicity of activated beta-catenin (MMTV-DN89beta-catenin). The relationships and dependencies of beta-catenin and cyclin D1 point to distinct, essential and sequential roles during alveologenesis. These results support the concept that both beta-catenin's and cyclin D1's actions are more sophisticated than simple acceleration of the cell cycle clock. These proteins are employed at critical junctures involving cell fate decisions that we speculate require specific types of cell cycle to traverse.
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PMID:Beta-catenin and cyclin D1: connecting development to breast cancer. 1471 77

The mechanisms by which growth factors cooperate with cell adhesion molecules to modulate epithelial cell motility remain poorly understood. Here, we investigated the role of the E-cadherin/catenin complex in insulin-like growth factor (IGF-I)-dependent cell migration and invasion. We used variants of the HCT-8 colon cancer family that differ in their expression of alphaE-catenin, an intracellular molecule that links the E-cadherin/catenin complex to the actin cytoskeleton. Migration was determined using a monolayer wound model and cell invasion by the penetration of the cells into type-I collagen gels. We showed that alpha-catenin-deficient cells were not able to migrate in cohort upon IGF-I stimulation. Transfection of these cells with alpha-catenin isoforms (alphaN- or alphaT-catenin) restored migratory response IGF-I. These results suggest that alpha-catenins are involved in the signal issued from the E-cadherin/catenin complex to regulate IGF-I-stimulated migration. In contrast, IGF-I promoted invasion of both alpha-catenin-deficient and alpha-catenin-expressing cells, indicating that alpha-catenin did not participate in the regulation of IGF-I-induced invasion. Inhibition of E-cadherin function by treatment with MB-2 monoclonal antibodies inhibited both IGF-I-dependent cell migration and invasion. Taken together, our results indicate that functional alpha-catenin is essential for migration but not for invasion, while E-cadherin is involved in both phenomena.
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PMID:Alpha-catenin is required for IGF-I-induced cellular migration but not invasion in human colonic cancer cells. 1496 Oct 74

Tumor development and progression is driven by the accumulation of somatic genetic alterations. Two major pathways have been suggested in colon tumorigenesis. The first one, the APC/B-catenin pathway consists of chromosomal imbalance (Instability) and therefore accumulation of different oncogenes and tumor supressor genes mutations associated with morphological changes. The second one is characterized by "DNA mismatch repair genes" damage with subsequent accumulation of somatic genetic predictive markers of distant metastasis using tissue microarrays in T2N0 colon cancer. In our series, we detected overexpression of survivin, CDK1, MIB1 and topoisomerase IIa in metastatic tumors.
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PMID:[Predictive molecular marker of distant metastasis in colorectal cancer]. 1502 5

The Adenomatous Polyposis coli (APC) gene is mutated or lost in most colon cancers, and the APC protein has emerged as a multifunctional protein that is not only involved in the Wnt-regulated degradation of -catenin, but also regulates cytoskeletal proteins and thus plays a role in cell migration, cell adhesion, and mitosis. The gut epithelium is uniquely dependent on an intricate balance between a number of fundamental cellular processes including migration, differentiation, adhesion, apoptosis, and mitosis. In this review, I discuss the molecular mechanisms that govern the various functions of APC and their relationship to the role of APC in colon cancer.
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PMID:The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium. 1547 44

Two major transcripts of lymphoid enhancer factor-1 (LEF-1) have been described. The long isoform with b-catenin binding domain functions as a transcriptional enhancer factor. The short isoform derives from an intronic promoter and exhibits dominant negative activity. Recently, alterations of LEF-1 isoforms distribution have been described in colon cancer. In the current study we employed a quantitative real-time reverse transcription PCR method (TaqMan) to analyze expression of LEF-1 isoforms in a large cohort of human tumor (n = 304) and tumor-free control samples (n = 56). The highest expression level of LEF-1 was found in carcinoma samples whereas brain cancer samples expressed little. Expression of LEF-1 was different in distinct cancer types. For example, the mRNA level of LEF-1 was lower in testicular tumor samples compared with tumor-free control samples. Besides epithelial cancers, significant LEF-1 expression was also found in hematopoietic cells. In hematological malignancies, overall LEF-1 level was higher in lymphocytic leukemias compared with myeloid leukemias and normal hematopoiesis. However, acute myeloid leukemia and acute lymphocytic leukemia showed a significantly increased fraction of the oncogenic LEF-1 compared with chronic lymphocytic leukemia and chronic myeloid leukemia. Taken together, these data suggest that LEF-1 is abundantly expressed in human tumors and the ratio of the oncogenic and the dominant negative short isoform altered not only in carcinomas but also in leukemia.
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PMID:Alterations of lymphoid enhancer factor-1 isoform expression in solid tumors and acute leukemias. 1575 19

Gastric cancer not located in the cardia still remains the second most common cancer worldwide, whereas adenocarcinoma of the cardia and gastroesophageal junction has been rapidly rising over the past two decades. Gastric cancer can be subdivided into two distinct pathologic entities, diffuse and intestinal, that have different epidemiologic and prognostic features. Various genetic and environmental factors play important roles in gastric carcinogenesis; both lead to either abnormal genes overexpression or inappropriate expression of normal genes, whose products confer the malignant phenotype. Advances have been made in the genetic changes mostly of the intestinal type; its development is probably a multistep process, as has been well described in colon cancer pathogenesis, whereas it remains tentative whether the diffuse type of malignancy follows an analogous progression. The most common genetic abnormalities in gastric cancer tend to be loss of heterozygosity of tumor suppressor genes, particularly of p53 or "Adenomatous Polyposis Coli" gene. The latter leads to gastric oncogenesis through changes related to E-cadherin-catenin complex, which plays a critical role in the maintenance of normal tissue architecture. Mutation of any of its components results in loss of cell-cell adhesion, thereby contributing to neoplasia. E-cadherin/CDH1 gene germline mutations have been recognized in families with an inherited predisposition to gastric cancer of the diffuse type. Amplification and/or overexpression of putative trophic factors have also been observed in gastric cancer. Finally, Helicobacter pylori (H. pylori) infection is also involved in gastric carcinogenesis through various mechanisms, thereby necessitating H. pylori eradication in patients with gastric cancer.
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PMID:New concepts of molecular biology on gastric carcinogenesis. 1600 83

Colon cancer evolves through epithelial cell deregulation and inappropriate proliferation. These histopathological characteristics are exemplified in the biochemical, immunohistochemical, genetic and epigenetic elements detected within colonic mucosa. Early detection is paramount for the prevention of colon cancer deaths. Aberrant crypt foci (ACF) are thought to be the earliest identifiable neoplastic lesions in the colon carcinogenetic model. The progression of ACF to polyp and, subsequently, to cancer parallels the accumulation of several biochemical alterations and mutations whereby a small fraction of ACF evolve to colon cancer. Recent data indicate that, not uncommonly, some ACF bypass the polyp stage in their carcinogenesis thus reinforcing the importance of their early detection and our understanding of their pathogenesis. Since ACF were first detected in carcinogen-treated mice, research efforts have focused on these microscopically visible lesions both in animal and human models. ACF show variable histological features, characterized by Kudo (20) and, therefore, can be grouped into differing categories by in vivo examination with high-magnification-chromoscopic-colonoscopy (HMCC). As expected, ACF are more frequently detected in distal animal and human colons coinciding with the geographic distribution of colorectal cancer (CRC). Various proteomic (Prot) markers may be altered within ACF suggesting possible prospective pathological changes. These markers include Calreticulin, Transgelin, Serotransferrin, Triphosphate isomerase and Carbonic anhydrase II. Other markers of importance include carcinoembryonic antigen (CEA), B-catenin, placental cadherin (P-cadherin), epithelial cadherin (E-cadherin), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2) and P16INK4a. Genetic mutations of K-ras, B-Raf APC and p53 have been demonstrated in ACF as well as the epigenetic alterations of CpG island methylation. Genomic instabilities (GI), illustrated by a higher GI Index (GII), microsatellite instability (MSI), loss of heterozygosity (LOH) and defects in mismatch repair (MMR) systems, are also expressed. These transformations may lead to the identification of the earliest pathological features initiating colon tumorigenesis. In this review, the advances in ACF research as precursors of CRCs are highlighted.
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PMID:Aberrant crypt foci. 1647 86


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