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)

Downregulation of carcinoembryonic antigen-related cell adhesion molecule (CEACAM1), a cell adhesion molecule with tumor suppressing properties has been observed in a high percentage of carcinomas of the endometrium and other malignancies. The mechanisms for the dysregulation and the role of hormones and cytokines on the expression of CEACAM1 in endometrial carcinomas is unknown. We therefore studied the effect of estradiol, medroxyprogesterone acetate (MPA), RU486, gamma-interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium ionophore A23187 on the expression in the non-expressing endometrial tumor cell lines Hec1B and Skut1B, respectively. No induction of CEACAM1 expression was observed in Hec1B endometrial adenocarcinoma cells in response to hormones and cytokines whereas treatment with TPA and calcium ionophore A23187 resulted in the strong expression of endogenous CEACAM1 on the mRNA and protein levels. In contrast, no induction of CEACAM1 expression was observed in endometrial mixed mesenchymal Skut1B cells. Studies of other members of the CEACAM family revealed that the re-expression in Hec1B carcinoma cells is restricted to CEACAM1 suggesting a cell type-specific and cell type-independent mechanism of CEACAM1 activation via the protein kinase C (PKC) pathway. Induction of CEACAM1 expression was dependent on protein kinase C protein synthesis and luciferase reporter assays with CEACAM1 promoter constructs demonstrated that the re-expression of CEACAM1 is regulated at the transcriptional level. This is the first report demonstrating that activators of PKC are able to specifically induce the expression of CEACAM1 in human carcinoma cells and our findings may provide a basis for the therapeutic inhibition of tumor growth in malignancies in which CEACAM1 is downregulated.
Carcinogenesis 2006 Mar
PMID:Stimulation of CEACAM1 expression by 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium ionophore A23187 in endometrial carcinoma cells. 1633 26

DNA hypermethylation in gene promoters is an epigenetic mechanism regulating gene expression in cellular immortalization, an important step in carcinogenesis. Previously, we studied the genes dysregulated during immortalization using spontaneously immortalized fibroblasts from patients with Li-Fraumeni syndrome (LFS), who carry a germline mutation in the tumor suppressor gene p53. We found that multiple interferon (IFN) signaling pathway genes were regulated by epigenetic silencing. In this study we focused on a key regulator of that pathway, the signal transducer and transcription activator 1 (Stat1) gene. Although Stat1 is downregulated after cellular immortalization and upregulated in immortal MDAH041 cells after 5-aza-2'-deoxycytidine (5-aza-dC) treatment, we detected no methylation of the Stat1 promoter region in these cells before or after immortalization. To analyze the function of Stat1 in immortalization, we expressed Stat1 in immortal MDAH041 cells by stable infection, expecting to induce IFN-regulated genes or cellular senescence or both. However, the overexpression of Stat1 alone was not sufficient to repress the proliferation rate of immortal MDAH041 cells or induce senescence in immortal MDAH041 cells. We concluded that factor(s) additional to Stat1 (whether IFN dependent or not) are required for the immortalization of LFS fibroblasts.
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PMID:Stat1 expression is not sufficient to regulate the interferon signaling pathway in cellular immortalization. 1642 44

To elucidate the influence of a glycyrrhizin therapy on hepatocarcinogenesis rate in interferon (IFN)-resistant hepatitis C, we retrospectively analyzed 1249 patients with chronic hepatitis with or without cirrhosis. Among 346 patients with high alanine transaminase value (twice or more of upper limit of normal), 244 patients received intravenous glycyrrhizin injection and 102 patients did not, after judgment of IFN resistance. Crude carcinogenesis rates in the treated and untreated group were 13.3%, 26.0% at the 5th year, and 21.5% and 35.5% at the 10th year, respectively (P = .0210). Proportional hazard analysis using time-dependent covariates disclosed that glycyrrhizin treatment significantly decreased the hepatocarcinogenesis rate (hazard ratio 0.49, 95% confidence interval 0.27-0.86, P = .014) after adjusting the background features with significant covariates. Glycyrrhizin injection therapy significantly decreased the incidence of hepatocellular carcinoma in patients with IFN-resistant active chronic hepatitis C, whose average aminotransferase value was twice or more of upper limit of normal after interferon.
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PMID:A long-term glycyrrhizin injection therapy reduces hepatocellular carcinogenesis rate in patients with interferon-resistant active chronic hepatitis C: a cohort study of 1249 patients. 1661 74

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-kappaB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1-/- Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1-/- background, spontaneously developed colorectal carcinomas carrying nuclear beta-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)gamma-/- SOCS1-/- mice and SOCS1-/- Tg mice treated with anti-IFNgamma antibody did not develop such tumors. STAT3 and NF-kappaB activation was evident in SOCS1-/- Tg mice, but these were not sufficient for tumor development because these are also activated in IFNgamma-/- SOCS1-/- mice. However, colons of SOCS1-/- Tg mice, but not IFNgamma-/- SOCS1-/- mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNgamma/STAT1 pathways.
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PMID:IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. 1671 19

Chronic infection of hepatitis C (HCV) and B virus (HBV) frequently causes viral hepatitis. Patients with chronic viral hepatitis are at risk for liver cirrhosis and even hepatocellular carcinoma. In patients with chronic hepatitis C, the most effective therapy is elimination of HCV with interferon (IFN). The most effective initial IFN therapy is the combination of pegylated IFN alpha-2b plus ribavirin. Forty-eight weeks of this combination therapy produces sustained viral response rates of approximately 50%. Moreover, several reports showed that long-term IFN therapy also reduced the risk of liver carcinogenesis. In patients with chronic hepatitis B, seroconversion from HBeAg to anti-HBe antibodies suppresses viral replication and attenuates the hepatitis. Twenty-four weeks of IFN therapy produces HBeAg seroconversion rates approximately 30%.
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PMID:[HCV-HBV infection]. 1683 49

Chronic inflammation induced by viral infections and their role in carcinogenesis is well recognized. Two hepatotropic viruses, hepatitis B and hepatitis C (HCV), have been linked worldwide to the development of hepatocellular carcinoma (HCC). Although orthotopic liver transplant offers the best chance for cure and long-term survival, the demand for organs far outweighs the supply. The incidence of HCC in the United States has increased over the past 3 decades. HCV-induced cirrhosis is believed to play a significant role in the rising rate of HCC. Therefore, primary measures to prevent HCC in HCV-infected patients are urgently needed. Numerous studies of the HCV HCC patient have considered primary treatment with interferon-based therapy. However, secondary prevention currently seems to carry more promise. This article evaluates and assesses various treatments for primary and secondary chemoprevention in the setting of HCV.
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PMID:Can therapy of hepatitis C affect the development of hepatocellular carcinoma? 1694 53

Following integration of human papillomavirus (HPV) into the host genome, overexpression of the viral oncogenes E6 and E7 requires loss of the transcriptional repressor functions of E2. A key step in HPV-related carcinogenesis is therefore clearance of residual viral episomes, which encode E2. As spontaneous loss of HPV-16 episomes in vitro is associated with increased expression of antiviral genes inducible by type I interferon (IFN), we used the W12 model to examine the effects of exogenous IFN-beta on cervical keratinocytes containing HPV-16 episomes as a result of 'natural' infection in vivo. In contrast to studies of cells transfected with HPV-31 or bovine papillomavirus, IFN-beta caused rapid reduction in numbers of HPV-16 episomes. This was associated with the emergence of cells bearing previously latent integrants, in which there was increased expression of E6 and E7. Our data indicate that integrated HPV-16 can exist in a minority of cells in a mixed population without exerting a selective advantage until episome numbers are reduced. The kinetics of cell death and changes in viral transcription and translation that we observed support a model where integrants are initially present in cells also containing episomes, with generalized episome clearance by IFN-beta resulting in integrant de-repression. We conclude that IFN-beta can hasten the transition from episomal to integrated HPV-16 in naturally infected cervical keratinocytes. Greater emphasis should be placed on episome loss in models of HPV-related carcinogenesis. We provide the strongest evidence to date that treating HPV-16 lesions by inducing an IFN response may cause clinical progression.
Carcinogenesis 2006 Nov
PMID:Interferon-beta treatment of cervical keratinocytes naturally infected with human papillomavirus 16 episomes promotes rapid reduction in episome numbers and emergence of latent integrants. 1697 73

An increasing number of tumour suppressor genes are induced by interferons (IFNs) and may play an important role in the control of cell proliferation induced by this cytokine. In addition, pathways triggered by both tumour suppressors and IFN converge as common targets for non-related tumour viruses. The inhibition of the IFN response by animal viruses is explained by the fundamental role that IFN plays to control virus infection. However, the reasons why many viruses, including those that do not require the replication of the host, target tumour suppressor pathways are varied and are still under investigation. Here we review those findings that support that tumour suppressors may have a role in the control of virus infection.
Carcinogenesis 2007 Jun
PMID:Control of virus infection by tumour suppressors. 1734 39

Inducible nitric-oxide synthase (iNOS) has been identified as a marker and mediator of disease in human colonic inflammation and carcinogenesis. Accordingly, identification of mediators that trigger iNOS in colon carcinoma/epithelial cells is an important topic of current research. Here we demonstrate that interleukin (IL)-22, a newly described member of the IL-10 cytokine family, potently synergizes with interferon (IFN)-gamma for iNOS expression in human DLD-1 colon carcinoma cells. Detection of both IL-22 receptor chains and STAT3 phosphorylation proved robust IL-22 responsiveness of these cells. Short interfering RNA technology identified STAT3 as being crucial for up-regulation of iNOS. Compared with IFNgamma, STAT1 phosphorylation by IL-22 was insufficient. IL-22 did not stabilize IL-1beta/tumor necrosis factor-alpha/IFNgamma-induced iNOS mRNA. IL-22 also failed to amplify expression of the prototypic IFNgamma-inducible parameters IL-18-binding protein and CXCL-10, indicating that IL-22 is not a general amplifier of IFNgamma functions. This assumption is furthermore supported by the observation that IL-22 was unable to enhance cellular activation of the pro-inflammatory transcription factor nuclear factor-kappaB. In contrast, IL-22 increased iNOS promoter activation as detected by using DLD-1 cells stably transfected with a corresponding 16-kb promoter construct (pNOS2(16)-Luc). IL-22 likewise enhanced iNOS in Caco-2 colon carcinoma cells. With IL-22 we introduce a novel potent determinant of iNOS expression in human colon carcinoma/epithelial cells. Considering the eminent functions of STAT3 and iNOS in inflammation and carcinogenesis, IL-22 may represent a novel target for immunotherapeutic intervention.
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PMID:The interleukin-22/STAT3 pathway potentiates expression of inducible nitric-oxide synthase in human colon carcinoma cells. 1743 34

Pathogenic mechanisms associated with Helicobacter pylori infection enhance susceptibility of the gastric epithelium to carcinogenic conversion. We have characterized the gene expression profiles of gastric biopsies from 69 French Caucasian patients, of which 43 (62%) were infected with H. pylori. The bacterium was detected in 27 of the 42 antral biopsies examined and in 16 of the 27 fundic biopsies. Infected biopsies were selected for the presence of chronic active gastritis, in absence of metaplasia and dysplasia of the gastric mucosa. Infected antral and fundic biopsies exhibited distinct transcriptional responses. Altered responses were linked with: (1) the extent of polymorphonuclear leukocyte infiltration, (2) bacterial density, and (3) the presence of the virulence factors vacA, babA2, and cagA. Robust modulation of transcripts associated with Toll-like receptors, signal transduction, the immune response, apoptosis, and the cell cycle was consistent with expected responses to Gram-negative bacterial infection. Altered expression of interferon-regulated genes (IFITM1, IRF4, STAT6), indicative of major histocompatibility complex (MHC) II-mediated and Th1-specific responses, as well as altered expression of GATA6, have previously been described in precancerous states. Upregulation of genes abundantly expressed in cancer tissues (UBD, CXCL13, LY96, MAPK8, MMP7, RANKL, CCL18) or in stem cells (IFITM1 and WFDC2) may reveal a molecular switch towards a premalignant state in infected tissues. Tissue microarray analysis of a large number of biopsies, which were either positive or negative for the cag-A virulence factor, when compared to each other and to noninfected controls, confirmed observed gene alterations at the protein level, for eight key transcripts. This study provides 'proof-of-principle' data for identifying molecular mechanisms driving H. pylori-associated carcinogenesis before morphological evidence of changes along the neoplastic progression pathway.
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PMID:Gene expression profiling in human gastric mucosa infected with Helicobacter pylori. 1764 99


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