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)

A cell-mediated mutagenesis assay employing cultured primary SENCAR keratinocytes for the metabolism of promutagens, and V-79 fibroblasts as target cells for the resulting genotoxic metabolites, was used to survey the effects of murine beta-interferon (IFN-beta) on 7,12-dimethylbenz[a]anthracene (DMBA) and benzo[a]pyrene (BP)-dependent mutagenesis and cytotoxicity. Pre-incubation of the keratinocyte cultures with greater than 100 units/ml IFN-beta, but not mock IFN, partially inhibited DMBA (25-60%) and BP (25-63%) dependent mutagenesis, but had little effect on the cytotoxicities of these agents. The level of inhibition was influenced by the length of keratinocyte pre-incubation with IFN-beta, and the concentration of IFN-beta, and the number of keratinocytes per nmol of promutagen. IFN-beta dependent inhibition of DMBA mutagenesis correlated with alterations in DMBA metabolism, including a decrease in the intra- and extracellular concentrations of the proximal promutagen (+/-) trans-DMBA-3,4-dihydrodiol.
Carcinogenesis 1985 Dec
PMID:Interferon-beta inhibits 7,12-dimethylbenz[a]anthracene-dependent mutagenesis in a keratinocyte cell-mediated mutation assay. 241 68

Aberrant proliferation of tumor cells characterizes cancer growth. Investigations of cellular growth control mechanisms have contributed to our understanding of carcinogenesis and to the identification of compounds with specific antitumor activity. Many cytokines have been found to act on melanoma tumors, either produced by the tumor cells themselves or by infiltrating host cells. Purified cytokines allowed direct comparison of the growth response between normal human melanocytes and malignant melanoma cells. The present paper summarizes results of a series of our own experiments not yet published and data from a review of the recent literature. Proliferation of normal human melanocytes is enhanced by several cytokines, including basic fibroblast growth factor (bFGF), melanoma growth stimulatory activity (MGSA), hepatocyte growth factor (HGF), and mast cell growth factor (MGF). Melanoma cells are additionally stimulated by epidermal growth factor (EGF)/transforming growth factor alpha (TGF-alpha) and nerve growth factor (NGF). Tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta 1 (TGF-beta 1), and interleukin (IL)-6 are all potent inhibitors of melanocyte growth, but they are less effective on melanoma cells or even stimulate their growth. Interferon (IFN)-alpha and IFN-gamma inhibited proliferation of melanoma cells but not of melanocytes, whereas IFN-beta showed antiproliferative effects in both cell types. These findings suggest an alteration in growth control mechanisms during melanocyte transformation and possibly play a role in melanoma pathogenesis.
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PMID:Growth control of melanoma cells and melanocytes by cytokines. 759 88

SENCAR mice develop more papillomas in two-stage skin carcinogenesis protocols if gamma interferon (IFN-gamma) is co-administered with 12-O-tetradecanoylphorbol-13-acetate (TPA) during the promotion phase. In the current study preparations of murine alpha, beta and gamma IFNs were surveyed for their abilities to modulate TPA-dependent promotion and induction of epidermal hyperplasia, inflammation and ornithine decarboxylase activity (ODC). Single or multiple i.p. administrations of IFN-alpha, -beta or -gamma (< or = 2500 units) did not induce epidermal hyperplasia, inflammation or ODC activity. Single or multiple i.p. administrations of IFN-alpha, -beta or -gamma (2500 units) to mice being topically promoted with 0.1 or 1 microgram of TPA did not alter the epidermal hyperplasia induced by the phorbol ester. The vascular permeability of the skin, as evaluated by the extravasation of Evans blue dye, was increased in a dose-dependent fashion by TPA over the range of 0.1-1 microgram. Treatment of mice promoted with 0.1 microgram of TPA with IFN-gamma (> or = 2500 units) significantly increased the skin's vascular permeability. Comparable effects were not obtained with IFN-beta (IFN-alpha not tested). Treatment of TPA-promoted mice with IFN-gamma, and to a lesser extent IFN-beta, weakly potentiated the TPA-dependent induction of epidermal ODC activity. Under conditions in which IFN-gamma had co-promoting activities in an initiation-promotion protocol, co-treatment of initiated mice with 1 microgram of TPA and IFN-alpha or -beta (100-5000 units) did not reproducibly alter tumor latency., or papilloma and carcinoma multiplicities. These findings suggest that the co-promoting activities of IFNs are restricted to the gamma class, and are not uniformly reflected by parameters commonly employed as short-term markers of tumor promotion.
Carcinogenesis 1993 Mar
PMID:Differential co-promoting activities of alpha, beta and gamma interferons in the murine skin two-stage carcinogenesis model. 845 12

In studying biological roles of interferon regulatory factor (IRF)-1 tumor suppressor in cervical carcinogenesis, we found that HPV E7 is functionally associated with IRF-1. Binding assays indicate a physical interaction between IRF-1 and HPV E7 in vivo and in vitro. The carboxyl-terminal transactivation domain of IRF-1 was required for the interaction. Transient co-expression of E7 significantly inhibits the IRF-1-mediated activation of IFN-beta promoter in NIH-3T3 cells. Co-transfection of E7 mutants reveals that the pRb-binding portion of E7 is necessary for the E7-mediated inactivation of IRF-1. It was next determined whether histone deacetylase (HDAC) is involved in the inactivation mechanism as recently suggested, where the carboxyl-terminal zinc finger domain of E7 associates with NURD complex containing HDAC. When trichostatin A, an inhibitor of HDAC, was treated, the repressing activity of E7 was released in a dose-dependent manner. Furthermore, the mutation of zinc finger abrogates such activity without effect on the interaction with IRF-1. These results suggest that HPV E7 interferes with the transactivation function of IRF-1 by recruiting HDAC to the promoter. The immune-promoting role of IRF-1 evokes the idea that our novel finding might be important for the elucidation of the E7-mediated immune evading mechanism that is frequently found in cervical cancer.
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PMID:Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7 oncoprotein. Implication for the E7-mediated immune evasion mechanism in cervical carcinogenesis. 1070 32

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

Infection with HPV (human papillomavirus) 16 is the cause of 50% or more of cervical cancers in women. HPV16 infection, however, is very common in young sexually active women, but the majority mount an effective immune response and clear infection. Approx. 10% of individuals develop a persistent infection, and it is this cohort who are at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma. Effective evasion of innate immune recognition seems to be the hallmark of HPV infections, since the infectious cycle is one in which viral replication and release is not associated with inflammation. Furthermore, HPV infections disrupt cytokine expression and signalling with the E6 and E7 oncoproteins particularly targeting the type I IFN (interferon) pathway. High doses of IFN can overcome the HPV-mediated abrogation of signalling, and this may be the basis for the therapeutic effects on HPV infections of immune-response modulators such as the imidazoquinolones that induce high levels of type I IFNs by activation of TLR (Toll-like receptor) 7. Using the unique W12 model of cervical carcinogenesis, some of these IFN-related interactions and their relevance in the selection of cells with integrated viral DNA in cancer progression have been investigated. Our data show that episome loss associated with induction of antiviral response genes is a key event in the spontaneous selection of cervical keratinocytes containing integrated HPV16. Exogenous IFN-beta treatment of W12 keratinocytes in which the majority of the population contain episomes results only in the rapid emergence of IFN-resistant cells, loss of episome-containing cells and a selection of cells containing integrated HPV16 in which the expression of the transcriptional repressor E2 is down-regulated, but in which E6 and E7 are up-regulated.
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PMID:HPV: from infection to cancer. 1803 Dec 45

Interferons (IFNs) have been used to treat mucosal lesions caused by human papillomavirus (HPV) infection, such as intraepithelial precursor lesions to cancer of the uterine cervix, genital warts or recurrent respiratory papillomatosis, to potentially reduce or eliminate replicating HPV plasmid genomes. Mucosal HPVs have evolved mechanisms that impede IFN-beta synthesis and downregulate genes induced by IFN. Here we show that these HPV types directly subvert a cellular transcriptional response to IFN-beta as a potential boost in infection. Treatment with low levels of human IFN-beta induced initial amplification of HPV-16 and HPV-11 plasmid genomes and increased HPV-16 or HPV-31 DNA copy numbers up to 6-fold in HPV-immortalized keratinocytes. IFN treatment also increased early gene transcription from the major early gene promoters in HPV-16, HPV-31 and HPV-11. Furthermore, mutagenesis of the viral genomes and ectopic interferon regulatory factor (IRF) expression in transfection experiments using IRF-1(-/-), IRF-2(-/-) and dual knockout cell lines determined that these responses are due to the activation of IRF-1 interaction with a conserved interferon response element demonstrated in several mucosal HPV early gene promoters. Our results provide a molecular explanation for the varying clinical outcomes of IFN therapy of papillomatoses and define an assay for the modulation of the HPV gene program by IFNs as well as other cytokines and signaling molecules in infection and therapy.
Carcinogenesis 2009 Aug
PMID:Interferon-beta treatment increases human papillomavirus early gene transcription and viral plasmid genome replication by activating interferon regulatory factor (IRF)-1. 1954 54

Cytochrome P450 1B1 (CYP1B1) catalyzes estrogen hydroxylation and activation of potential carcinogens. Here we explored the role of CYP1B1 in endometrial carcinogenesis. Immunohistochemical staining of endometrial carcinomas showed that CYP1B1 is up-regulated in endometrial cancers. To understand the functional significance of CYP1B1 up-regulation in endometrial cancers with regard to tumorigenesis, we used small interfering RNA-mediated approach to knockdown CYP1B1 in endometrial carcinoma cell line followed by functional assays. Further, to understand the molecular basis of the role of CYP1B1 in endometrial carcinomas, we profiled the expression of key pathway-specific genes and identified several components of cell cycle, apoptosis, and cell adhesion pathways that are potentially regulated by CYP1B1. CYP1B1 depletion in endometrial carcinoma cells leads to decreased cellular proliferation and induces G(0)-G(1) cell cycle arrest. Significantly, CYP1B1 knockdown leads to down-regulated expression of cyclin E1, S-phase kinase-associated protein 2 (SKP2), minichromosome maintenance complex component 4 (MCM4), and RAD51 and up-regulation of p27(Kip1). Also, we identified cyclin E-binding protein (CEBP1) as a novel CYP1B1 target. Attenuation of CYP1B1 expression in endometrial carcinoma cells induces apoptosis and increases expression of IFN-beta (IFNbeta), granzyme A (GRZA), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Importantly, CYP1B1 depletion decreased the invasive potential of the endometrial cancer cells and expression of melanoma cell adhesion molecule (MCAM). In conclusion, our data suggest that CYP1B1 up-regulation plays a crucial role in endometrial carcinogenesis by targeting multiple pathways. We speculate that CYP1B1 inhibition in endometrial carcinomas could be a useful therapeutic approach as it regulates several potential anticancer targets like cyclin E1, Skp2, and TRAIL.
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PMID:Functional significance of cytochrome P450 1B1 in endometrial carcinogenesis. 1969 Jan 33