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)

Signaling from transforming growth factor-beta (TGF-beta) through its unique transmembrane receptor serine-threonine kinases plays a complex role in carcinogenesis, having both tumor suppressor and oncogenic activities. Tumor cells often escape from the antiproliferative effects of TGF-beta by mutational inactivation or dysregulated expression of components in its signaling pathway. Decreased receptor function and altered ratios of the TGF-beta type I and type II receptors found in many tumor cells compromise the tumor suppressor activities of TGF-beta and enable its oncogenic functions. Recent identification of a family of intracellular mediators, the Smads, has provided new paradigms for understanding mechanisms of subversion of TGF-beta signaling by tumor cells. In addition, several proteins recently have been identified that can modulate the Smad-signaling pathway and may also be targets for mutation in cancer. Other pathways such as various mitogen-activated protein kinase cascades also contribute substantially to TGF-beta signaling. Understanding the interplay between these signaling cascades as well as the complex patterns of cross-talk with other signaling pathways is an important area of investigation that will ultimately contribute to understanding of the bifunctional tumor suppressor/oncogene role of TGF-beta in carcinogenesis.
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PMID:Role of transforming growth factor-beta signaling in cancer. 1128 52

Transforming growth factor-beta is believed to play a dual role in carcinogenesis. Through its ability to inhibit cellular proliferation it suppresses tumor development in its early stages, but in the course of tumor progression malignant cells often acquire resistance to growth inhibition by transforming growth factor-beta and themselves secrete large amounts of this cytokine. Transforming growth factor-beta furthers malignant progression in two ways: for one, it acts on nontransformed cells present in the tumor mass to suppress antitumor immune responses and to augment angiogenesis. Secondly, it promotes invasion and the formation of metastases in a cell-autonomous manner that requires transforming growth factor-beta signaling activity, albeit at reduced levels, to be present in the tumor cells themselves.
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PMID:The transforming growth factor-beta signaling pathway in tumorigenesis. 1114 90

To elucidate involvement of the transforming growth factor-beta (TGF-beta) signaling pathway in endogenous and exogenous liver carcinogenesis, we investigated mutations of TGF-beta receptor type II (TGF-betaRII), Smad2 and Smad4 genes, and expression of TGF-betaRII in hepatocellular carcinomas (HCCs) induced by a choline-deficient L-amino acid-defined (CDAA) diet and by N-nitrosodiethylamine (DEN). Male Fischer 344 rats received a CDAA diet continuously and HCCs were sampled after 75 weeks. Administration of DEN was followed by partial hepatectomy (PH), with colchicine to induce cell cycle disturbance and a selection pressure regimen, HCCs being obtained after 42 weeks. Total RNAs were extracted from individual HCCs and mutations in TGF-betaRII, Smad2 and Smad4 were investigated by reverse transcription (RT)-polymerase chain reaction (PCR)-restriction-single-strand conformation polymorphism (SSCP) analysis followed by sequencing analysis. Mutations of Smad2 were detected in 2 out of 12 HCCs (16.7%) induced by the CDAA diet, a GGT-to-GGC transition (Gly to Gly) at codon 30 and a TCT-to-GCT (Ser to Ala) transversion at codon 118, without any TGF-betaRII or Smad4 alterations. No mutations of TGF-betaRII, Smad2 and Smad4 were encountered in eleven HCCs induced by the exogenous carcinogen. Semi-quantitative RT-PCR revealed reduced expression of TGF-betaRII in 2 HCCs (16.7%) without Smad2 mutations out of 12 HCCs induced by the CDAA diet and none of 11 induced by DEN. These results suggest that the TGF-beta signaling pathway may be disturbed in endogenous liver carcinogenesis in rats.
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PMID:Alterations of the transforming growth factor-beta signaling pathway in hepatocellular carcinomas induced endogenously and exogenously in rats. 1117 39

We assessed the possible association between CagA+ Helicobacter pylori infection and gastric carcinogenesis in gastric cancer patients. Gastric biopsy specimens were obtained from 64 patients with gastric cancer and were histologically classified into intestinal and diffuse types. H. pylori infection was determined by cultivation, flaA-PCR and serum antibody against CagA. p53, BAX and transforming growth factor-beta-RII (TGFbeta-RII) gene mutations were analyzed by PCR-SSCP and direct sequencing. Intestinal and diffuse types of cancer were detected in 45 and 19 patients, respectively. H. pylori infection was found in 55 (85.9%) of 64 patients. There was no significant difference in H. pylori positivity between intestinal and diffuse types. However, the CagA antibody was positive in 15 (78.9%) of 19 patients with the diffuse type and in 22 (48.9%) of 45 patients with the intestinal type (p = 0.030). Among the 55 H. pylori-positive cases, 11 (29.7%) of the 37 patients in the CagA+ group were found to have p53 alterations, compared with 2 (11.1%) in the 18 CagA- group (p = 0.182). Moreover, among the 64 gastric cancer patients, p53 alterations were more frequently found in the CagA+ group (29.7%) than in the H. pylori-positive CagA- and H. pylori-negative groups (7.4%; p = 0.033). BAX gene mutations were found in 19 (29.7%) of 64 patients and there was no relationship among CagA seropositivity, cancer stages and histopathological phenotypes. In contrast, the TGFbeta-RII gene mutation was only detected in one CagA- patient. The results suggest that CagA+ H. pylori infection may have an important role in the development of gastric cancer patients with p53 mutations
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PMID:Association between CagA+ Helicobacter pylori infection and p53, bax and transforming growth factor-beta-RII gene mutations in gastric cancer patients. 1125 69

Loss of heterozygosity (LOH) on chromosome 3p is a common event in cervical cancer and typically occurs in a dispersed pattern involving several loci. This implies that more than one resident tumor-suppressor gene is involved in the genesis of these tumors; however, specific targets remain to be identified. The region of 3p14.2-pter encompasses a region of frequent loss and contains at least three tumor-suppressor genes: fragile histidine triad (FHIT), transforming growth factor-beta receptor II (T beta R-II), and Von Hippel-Lindau. To identify those loci within 3p14.2-pter that are important in cervical cancer, invasive tumors were first subjected to high-density LOH analysis. With 25 microsatellite markers, LOH was detected in seven of 15 cervical carcinomas (47%). Losses always included markers mapping to 3p22, and markers at this location were exclusively lost in two tumors, implicating this as a site of a cervical tumor-suppressor gene. Because it is a known tumor-suppressor gene located at 3p22 and thus a potential target for inactivation in these tumors, the T beta R-II gene was subsequently screened for mutation and altered expression levels. Whereas no tumor-derived mutations were detected in any of the tumors, six of ten tumors showed T beta R-II transcript levels reduced by > or = 50% when compared with normal cervical epithelium. Nine of 15 (60%) tumors exhibited LOH at 3p22 or reduced expression of T beta R-II, suggesting that reduced T beta R-II levels contribute to cervical tumorigenesis. Two cases exhibited silent germline polymorphisms of T beta R-II: one corresponding to a C1167T transversion and the other to an A1266G transition. The FHIT gene, which is located at 3p14.2, also frequently incurred LOH and abnormal transcription in these tumors. LOH of FHIT was observed in five of the 15 tumors analyzed. Neither mutations nor homozygous deletions of FHIT were detected in the tumors. However, aberrantly short transcripts of the FHIT gene were evident in six of nine (67%) tumors. Only one of these also displayed LOH, indicating that this gene was altered in at least 10 of 15 (67%) tumors. These results provide evidence that the inactivation of two known tumor-suppressor genes, TbetaR-II and FHIT, on chromosome 3p is involved in cervical carcinogenesis. Mol. Carcinog. 30:159--168, 2001.
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PMID:Chromosome 3p tumor-suppressor gene alterations in cervical carcinomas. 1130 76

To evaluate the genetic factors of familial predisposition to gastric cancer, genetic alterations in the surgically resected stomach samples from gastric-cancer-prone families were investigated. Familial gastric cancer (FGC) was defined as gastric cancer occurring in a family with 3 or more gastric cancer patients over at least two successive generations. We examined replication error (RER) of six microsatellite markers and screened mutations of the 10-(A) repeat sequence in the transforming growth factor-beta receptor type II (TGF-betaRII) gene in individuals from seven unrelated FGC families. Three cases showed RER at one of the six (CA)n microsatellite markers but the other 4 cases showed no RER at any of these loci. No mutation was found in the 10-(A) repeat of the TGF-betaRII gene. Additionally, no germline mutation was found by polymerase chain reaction-single strand conformation polymorphism in exons 1-16 of E-cadherin, exons 5-8 of p53 and in the mutation cluster region of APC. These results indicate that disorders in the DNA mismatch repair system, E-cadherin, p53 and APC may be infrequently involved in the carcinogenesis of Japanese FGC.
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PMID:Absence of microsatellite instability and germline mutations of E-cadherin, APC and p53 genes in Japanese familial gastric cancer. 1139 52

We studied the effect of oral administration of resveratrol, a natural constituent of grapes, on tumorigenesis in Min mice. Min mice are congenic mice genetically predisposed to develop intestinal tumors as a result of a mutation of the Apc gene. Resveratrol (0.01% in the drinking water containing 0.4% ethanol) was administered for seven weeks to Min mice starting at five weeks of age. The control group was fed the same diet and received water containing 0.4% ethanol. Resveratrol prevented the formation of colon tumors and reduced the formation of small intestinal tumors by 70%. Comparison of the expression of 588 genes in the small intestinal mucosa showed that resveratrol downregulated genes that are directly involved in cell cycle progression or cell proliferation (cyclins D1 and D2, DP-1 transcription factor, and Y-box binding protein). In addition, resveratrol upregulated several genes that are involved in the recruitment and activation of immune cells (cytotoxic T lymphocyte Ag-4, leukemia inhibitory factor receptor, and monocyte chemotactic protein 3) and in the inhibition of the carcinogenic process and tumor expansion (tumor susceptibility protein TSG101, transforming growth factor-beta, inhibin-beta A subunit, and desmocollin 2). Our data highlight the complexity of the events associated with intestinal tumorigenesis and the multiplicity of the molecular targets of resveratrol. The high potency and efficacy of resveratrol support its use as a chemopreventive agent in the management of intestinal carcinogenesis.
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PMID:Resveratrol inhibits intestinal tumorigenesis and modulates host-defense-related gene expression in an animal model of human familial adenomatous polyposis. 1158 90

The transforming growth factor-beta (TGF-beta)-Smad signaling pathway has an important role in carcinogenesis. To study the frequency and mechanism of functional impairment of this pathway in human gastrointestinal cancers, we used a reporter assay to examine the response of 38 cell lines (11 colorectal, 9 pancreatic, 10 gastric, and 8 hepatic cancers) to TGF-beta. We then analyzed TGF-beta type II receptor (T beta RII) gene, immunoblots of Smad4, and restoration of the pathway by rescuing T beta R or Smad. We observed impaired signaling in 91% of colorectal, 67% of pancreatic, and 40% of gastric cancer cell lines, but in none of the hepatic cancer cells. We suggest that this pathway does not function as a tumor suppressor in hepatic carcinogenesis. The impairment is due to inactivation of T beta RII and Smad4 in colorectal and pancreatic cancers. However, because the signal was not recovered by rescuing T beta R or Smad genes in TGF-beta-response-defective gastric cancer cell lines, we suggest that novel molecules or mechanisms are involved in the impaired pathway in some gastric cancers.
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PMID:Systematic analysis of the TGF-beta-Smad signaling pathway in gastrointestinal cancer cells. 1171 79

Bone morphogenetic protein-6 (BMP-6) is a member of the transforming growth factor-beta superfamily. In murine skin, BMP-6 is highly expressed in postmitotic keratinocytes from day 15.5 p.c. till day 6 p.p. Expression in adult skin remains at very low levels, but pathological conditions such as wounding induce the expression of BMP-6. We demonstrate that tumor promotion by TPA (12-O-tetradecanoylphorbol-13-acetate) also induces expression of BMP-6 in suprabasal keratinocytes. This induction is due to post-transcriptional regulation since the level of BMP-6 mRNA remained unchanged. We performed two-stage skin carcinogenesis experiments with transgenic mice epidermally overexpressing BMP-6. These mice display augmented mitotic indices in normal and TPA-treated epidermis when compared to controls. Despite this hyperproliferation, BMP-6 transgenics showed a delayed development and strong suppression of benign and malignant skin tumor formation. In order to resolve this paradox we determined apoptotic frequencies as well as the expression of constituents of AP-1 (activator protein-1) which is essential for tumor promotion. A higher rate of apoptotic keratinocytes was detectable in transgenic mice versus controls and a downregulation of mRNA for jun/fos family members in transgenic skin after TPA-treatment. Thus expression of BMP-6 augments apoptosis and downregulates the transcription of AP-1 family members thereby establishing tumor resistance.
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PMID:Overexpression of bone morphogenetic protein-6 (BMP-6) in murine epidermis suppresses skin tumor formation by induction of apoptosis and downregulation of fos/jun family members. 1175 54

Dietary phenolic substances including resveratrol, a stillbene compound, are found in several fruits and vegetables, and these compounds have been reported to have anti-oxidant, anti-inflammatory and antitumorigenic activities. However, the molecular mechanisms underlying the antitumorigenic or chemopreventive activities of these compounds remain largely unknown. The expression of NAG-1 [non-steroidal anti-inflammatory (NSAID) drug-activated gene-1], a member of the transforming growth factor-beta (TGF-beta) superfamily, has been shown to be associated with pro-apoptotic and antitumorigenic activities. Here, we have demonstrated that resveratrol induces NAG-1 expression and apoptosis in a concentration-dependent manner. Resveratrol increases the expression of p53, tumor suppressor protein, prior to NAG-1 induction, indicating that NAG-1 expression by resveratrol is mediated by p53 expression. We also show that the p53 binding sites within the promoter region of NAG-1 play a pivotal role to control NAG-1 expression by resveratrol. Derivatives of resveratrol were examined for NAG-1 induction, and the data suggest that resveratrol-induced NAG-1 and p53 induction is not dependent on its anti-oxidant activity. The data may provide linkage between p53, NAG-1 and resveratrol, and in part, a new clue to the molecular mechanism of the antitumorigenic activity of natural polyphenolic compounds.
Carcinogenesis 2002 Mar
PMID:Resveratrol enhances the expression of non-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing the expression of p53. 1189 57


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