Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nodal and BMP signaling pathways network with WNT signaling pathway during embryogenesis and carcinogenesis. CER1 (Cerberus 1) and GREM3 (CKTSF1B3 or CER2) inhibit NODAL signaling through ACVR1B (ALK4) or ACVR1C (ALK7) to SMAD2 or SMAD3. GREM1 (CKTSF1B1) inhibits BMP signaling through BMPR1A (ALK3), BMPR1B (ALK6) or ACVR1 (ALK2) to SMAD1, SMAD5 or SMAD8. CER1, GREM1 and GREM3 are DAN domain (DAND) family members; however, transcriptional regulation of DAND family members by canonical WNT signaling pathway remains unclear. We searched for the TCF/LEF-binding site within the promoter region of DAND family genes, including CER1, GREM1, GREM2, GREM3 and NBL1. Because triple TCF/LEF-binding sites were identified within human CER1 promoter by using bioinformatics and human intelligence, comparative genomics analyses on CER1 orthologs were further performed. Chimpanzee CER1 gene, encoding 267-amino-acid protein, was identified within NW_111298.1 genome sequence. XM_528542.1 was not a correct coding sequence for chimpanzee CER1. Primate CER1 orthologs were significantly divergent from rodent Cer1 orthologs. Three TCF/LEF-binding sites within human CER1 promoter were conserved in chimpanzee CER1 promoter, two in cow and dog Cer1 promoters, but not in rodent Cer1 promoters. Binding sites for NODAL signaling effectors, SMAD3/SMAD4 and FOXH1, were also conserved among human, chimpanzee, cow and dog CER1 promoters. CER1 orthologs were evolutionarily conserved target of WNT and NODAL signaling pathways in non-rodent mammals. Human CER1 mRNA was expressed in embryonic stem (ES) cells in the undifferentiated state and in the early endodermal lineage. CER1 upregulation in human ES cells leads to Nodal signaling inhibition associated with differentiation of human ES cells. Primate CER1 orthologs, playing a pivotal role during early embryogenesis, underwent protein evolution as well as promoter evolution. These facts indicate that molecular evolution of CER1 orthologs contributes to the significantly divergent scenarios of early embryogenesis in primates and rodents.
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PMID:CER1 is a common target of WNT and NODAL signaling pathways in human embryonic stem cells. 1659 63

The role of the natural dietary flavonoid chemical quercetin (an antioxidant) in the prevention and treatment of colon cancer is receiving a great deal of attention. However, little is known about the molecular mechanisms of action of this flavonoid. In the present study, whole genome DNA microarrays were used to evaluate the effect of quercetin on gene expression in the CO115 colon-adenocarcinoma cell line with the completely deleted chromosome 18 harbouring the SMAD4 tumour-suppressor gene related to colon carcinogenesis. The study demonstrated that quercetin, widely present in fruit and vegetables, inhibited the growth of CO115 cells at 100 microM concentration in both the G(1)/S and the G(2)/M phases by modulating cell-cycle and apoptosis-related genes. Differential changes in accumulation of transcripts analysed for cells treated with 100 microM quercetin for 24 and 48 h in three independent repeated experiments revealed 5060-7000 differentially expressed genes. This means that quercetin probably does have a broad modulatory effect on gene expression in colon cancer. Out of these differentially expressed genes, the expression of 35 and 23 unique set of genes involved in cell-cycle control, apoptosis and xenobiotic metabolism were significantly altered after 24 and 48 h quercetin treatment respectively. Our results represent a novel aspect of the biological profile of quercetin that induces cell-cycle arrest through modulation of cell-cycle-related and apoptosis genes. The present study demonstrates a new step in elucidating the underlying molecular mechanisms of the antitumour action of quercetin, which could become a chemopreventive or chemotherapeutic agent for colon cancer.
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PMID:A preliminary investigation demonstrating the effect of quercetin on the expression of genes related to cell-cycle arrest, apoptosis and xenobiotic metabolism in human CO115 colon-adenocarcinoma cells using DNA microarray. 1664 May 4

It has been well documented that there are two major pathways in colorectal carcinogenesis. One is the chromosomal instability pathway (adenoma-carcinoma sequence), which is characterized by allelic losses on chromosome 5q (APC), 17p (p53), and 18q (DCC/SMAD4), and the other is a pathway that involves microsatellite instability. Recent progress in molecular biology, however, has shown that colorectal carcinogenesis is not necessarily clearly divided into these two pathways, but is in fact more complicated. Other routes, including the transforming growth factor-beta/SMAD pathway, the serrated pathway, and the epigenetic pathway, have been reported. Cross talk among these pathways has also been reported. In the invasion and metastasis steps of colorectal cancers, many more genes have now been identified as being involved in proteolysis, adhesion, angiogenesis, and cell growth. Recently accumulated evidence indicates that colorectal cancer is a genetically heterogeneous and complicated disease.
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PMID:Colorectal cancer: genetics of development and metastasis. 1669 51

There is increasing evidence that epithelial to mesenchymal transition (EMT) is involved in cancer progression. Because local invasion and metastasis occurs early in the pathogenesis of esophageal adenocarcinoma, we hypothesized that EMT may be important in this disease. Using immunohistochemistry in a well-characterized set of adenocarcinoma tissues, we showed down-regulation of epithelial markers (E-cadherin and cytokeratin 18) and up-regulation of mesenchymal markers (vimentin and alpha-smooth muscle actin) with concomitant transforming growth factor-beta1 (TGF-beta1) expression at the invasive margin compared with the central tumor. A panel of esophageal cell lines was examined for the ability of TGF-beta1 to induce EMT in vitro. TE7 cells were selected as a model because TGF-beta1 (0-5 ng/mL) treatment induced morphologic and molecular expression changes suggestive of EMT. In TE7 cells, these TGF-beta1-induced changes were reversed by 100 ng/mL of bone morphogenetic protein 7 (BMP7), another member of the TGF-beta1 superfamily. EMT was mediated via canonical TGF-beta1 signaling with concomitant up-regulation of SMAD-interacting protein 1. Alterations in functional variables (aggregation, wounding, motility, and invasion) following TGF-beta1 treatment were consistent with a more invasive phenotype. These functional changes were reversed by BMP7 and SMAD4 RNA interference in vitro. These data suggest that TGF-beta1-mediated EMT may be relevant in esophageal carcinogenesis.
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PMID:In vivo and in vitro evidence for transforming growth factor-beta1-mediated epithelial to mesenchymal transition in esophageal adenocarcinoma. 1701 15

Mechanisms of cellular transformation associated with human papillomavirus type 5 (HPV5), which is responsible for skin carcinomas in epidermodysplasia verruciformis (EV) patients, are poorly understood. Using a yeast two-hybrid screening and molecular and cellular biology experiments, we found that HPV5 oncoprotein E6 interacts with SMAD3, a key component in the transforming growth factor beta1 (TGF-beta1) signaling pathway. HPV5 E6 inhibits SMAD3 transactivation by destabilizing the SMAD3/SMAD4 complex and inducing the degradation of both proteins. Interestingly, the E6 protein of nononcogenic EV HPV9 failed to interact with SMAD3, suggesting that downregulation of the TGF-beta1 signaling pathway could be a determinant in HPV5 skin carcinogenesis.
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PMID:Human papillomavirus type 5 E6 oncoprotein represses the transforming growth factor beta signaling pathway by binding to SMAD3. 1702 Sep 41

To investigate the effect of DPC4 gene on invasion and metastasis of colorectal carcinoma cells, the expression of DPC4 was detected in sixty-three samples of colorectal tumors and seven cases of colorectal mucosa. The biological behavior of tumors expressing DPC4 was evaluated (including tumor staging, differentiation degree and metastasis). pcDNA3.1-DPC4 plasmid was constructed and transferred into HCT116 cells not expressing DPC4. The cell models (DPC4(+)-HCT116) steadily expressing DPC4 were obtained. Compared with HCT116 and pcDNA3.1-HCT116 cells, the doubling time of DPC4(+)-HCT116 cells was lengthened obviously (P<0.01), the apoptosis rate of DPC4(+)-HCT116 cells was significantly increased (PP<0.01), the cloning efficiency, cell adherency, migration and invasion ability of DPC4+-HCT116 cells were dropped obviously (P<0.01). The number of cancer nodules was decreased significantly in abdominal cavity and liver of the nude mice inoculated with DPC4(+)-HCT116 cells. The activity of MMP-9 and MMP-2 was detected by gelatin zymography. In comparison with HCT116 and pcDNA3.1-HCT116 cells, the activity of MMP-9 was decreased in DPC4(+)-HCT116 cells. Therefore, the down-regulation of DPC4 expression may be associated with the carcinogenesis of colorectal carcinoma. DPC4 may inhibit the proliferation of colon cancer cell by restraining growth and inducing apoptosis, and the invasion and metastasis of colorectal carcinoma cells. MMP-9 may be one of the downstream target genes regulated by DPC4.
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PMID:Effect of DPC4 gene on invasion and metastasis of colorectal carcinoma cells. 1715 82

Colorectal cancer is a disease that originates from the neoplastic transformation of epithelial cells of the colon and rectum, as a result of the accumulation of genetic and epigenetic aberrations. At least four sequential genetic changes, affecting one oncogene (KRAS) and three tumor suppressor genes (APC, SMAD4 and TP53), are required for the development of colorectal cancer. Abundant experimental studies and epidemiological data, as well as several human clinical trials suggest a protective effect of Vitamin D against colon carcinogenesis. Hypercalcemia, a side effect of natural Vitamin D, has currently restricted its therapeutic use; however, the development of new synthetic analogs with reduced hypercalcemic activity is promising for cancer therapy and prevention. Extensive research to elucidate the mechanisms underlying the anti-cancer action of Vitamin D is being undertaken. Understanding the complex molecular and cellular networks induced by Vitamin D or its analogs will improve the use of these compounds for the prevention and treatment of colorectal cancer.
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PMID:Colorectal cancer: potential therapeutic benefits of Vitamin D. 1715 47

We report the molecular characterization of 8 primary gastric carcinomas, corresponding xenografts, and 2 novel gastric carcinoma cell lines. We compared the tumors and cell lines, with respect to histology, immunohistochemistry, copy number, and hypermethylation of up to 38 genes using methylation-specific multiplex ligation-dependent probe amplification, and TP53 and CDH1 mutation analysis where relevant. The primary tumors and xenografts were histologically comparable and shared expression of 11 of 14 immunohistochemical markers (E-cadherin, beta-catenin, COX-2, p53, p16, TFF1, cyclin E, MLH1, SMAD4, p27, KLK3, CASR, CHFR, and DAPK1). Gains of CASR, DAPK1, and KLK3--not yet described in gastric cancer--were present in the primary tumors, xenografts, and cell lines. The most prominent losses occurred at CDKN2A (p16), CDKN2B (p15), CDKN1B (p27/KIP1), and ATM. Except for ATM, these losses were found only in the cell line or xenograft, suggesting an association with tumor progression. However, examination of p16 and p27 in 174 gastric cancers using tissue microarrays revealed no significant correlation with tumor stage or lymph node status. Further losses and hypermethylation were detected for MLH1, CHFR, RASSF1, and ESR, and were also seen in primary tumors. Loss of CHFR expression correlated significantly with the diffuse phenotype. Interestingly, we found the highest rate of methylation in primary tumors which gave rise to cell lines. In addition, both cell lines harbored mutations in CDH1, encoding E-cadherin. Xenografts and gastric cancer cell lines remain an invaluable research tool in the uncovering of the multistep progression of cancer. The frequent gains, losses, and hypermethylation reported in this study indicate that the involved genes or chromosomal regions may be relevant to gastric carcinogenesis.
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PMID:Molecular analysis of primary gastric cancer, corresponding xenografts, and 2 novel gastric carcinoma cell lines reveals novel alterations in gastric carcinogenesis. 1737 10

Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been revealed. High up in the list of colorectal cancer lesions are APC (adenomatous polyposis coli), K-ras, Smad4 (or DPC4-deleted in pancreatic cancer 4) and p53 genes. All these molecules are part of important pathways for the regulation of cell proliferation and apoptosis and as a result perturbation of these processes lead to carcinogenesis. The ubiquitin-proteasome system (UPS) is comprised of a multi-unit cellular protease system that regulates several dozens of cell proteins after their ligation with the protein ubiquitin. Given that among these proteins are regulators of the cell cycle, apoptosis, angiogenesis, adhesion and cell signalling, this system plays a significant role in cell fate and carcinogenesis. UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma. Cyclooxygenase-2 (Cox-2) is the inducible form of the enzyme that metabolizes the lipid arachidonic acid to prostaglandin H2, the first step of prostaglandins production. This enzyme is up-regulated in colorectal cancer and in several other cancers. Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population. NSAIDs have also Cox-independent anti-proliferative effects. Targeted therapies, the result of increasingly understanding carcinogenesis in the molecular level, have entered the field of anti-neoplastic treatment and are used by themselves and in combination with chemotherapy drugs. Combinations of targeted drugs have started also to be investigated. This article reviews the molecular pathogenesis of colorectal cancer, the roles of UPS and Cox-2 in it and puts forward a rational for their combined inhibition in colorectal cancer treatment.
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PMID:Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2. 1748 76

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-beta might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFbeta and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFbeta surface receptors. Cells were treated with TGFbeta1 and separated into cytosolic/nuclear fractions for western blotting with phospho-SMAD2, SMAD 2, 4 phospho-ATP-dependent tyrosine kinases (Akt), Akt and PTEN antibodies. PTEN mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative (DN) K-RAS construct. TGFbeta increased phospho-SMAD2 in both cytosolic and nuclear fractions. PD98059 treatment further increased phospho-SMAD2 in the nucleus of both pancreatic cell lines, and DN-K-RAS further improved SMAD translocation in K-RAS mutant CAPAN cells. TGFbeta treatment significantly suppressed PTEN protein levels concomitant with activation of Akt by 48 h through transcriptional reduction of PTEN mRNA that was evident by 6 h. TGFbeta-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFbeta. TGFbeta-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFbeta-induced transcriptional down-regulation of the tumor suppressor PTEN in a SMAD4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers.
Carcinogenesis 2007 Nov
PMID:RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells. 1763 24


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