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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethinylestradiol (EE) has evident paradoxical effects on cancer risk for human breast and hepatic cancer which parallel in some respects its effects on estrogen-induced neoplasms in the hamster kidney and liver. EE has been shown to be only weakly carcinogenic in the hamster kidney, but the most potent carcinogenic estrogen in the hamster liver following prolonged treatment. Unexpectedly, when EE and potent carcinogenic estrogens, such as diethylstilbestrol (DES), 17beta-estradiol (E2) and Moxestrol (MOX), are administered concomitantly, estrogen-induced carcinogenesis in the kidney is completely prevented. In studying this novel finding, we found that, compared with E2 exposure alone, EE at 0.05 and 1.0 nM significantly (P < 0.001) inhibited the rise in proliferation of cultured primary hamster proximal renal tubular (PRT) cells in the presence of E2 (1.0 nM). Consistent with these findings, combined EE + DES treatment for 5.0 months reduced hamster kidney c-myc, c-fos and c-jun RNA expression to 43, 37 and 52%, respectively, compared with levels observed after DES treatment alone. Interestingly, TAM + DES treatment for the same period also resulted in the same low level of RNA expression of these proto-oncogenes. c-MYC, c-FOS and c-JUN protein products were comparably reduced after either EE + DES or TAM + DES treatment. It appears that c-fos expression and c-FOS protein levels in the hamster kidney were more responsive to TAM inhibition. These data demonstrate that EE possesses unique anti-tumorigenic properties in vivo in the hamster kidney. Additionally, the observed anti-estrogen-like effect of EE on cell proliferation of cultured PRT cells suggests that EE may interfere critically with estrogen receptor (ER)-mediated mitogenic pathway(s) affected by potent carcinogenic estrogens, thus preventing subsequent gene dysregulation and, hence, tumor development. Based on competition studies, the differential binding of EE to hamster kidney ER relative to that of the other estrogens (E2, DES, MOX) appears not to contribute to the prevention of estrogen carcinogenesis at this organ site by EE.
Carcinogenesis 1998 Mar
PMID:Prevention of estrogen carcinogenesis in the hamster kidney by ethinylestradiol: some unique properties of a synthetic estrogen. 952 82

The effects of space restriction and water-immersion stress on epithelial cell proliferation in the digestive tract, with special attention to the esophagus, stomach and duodenum, in 8-week-old SD male rats were examined. Histological assessment revealed spotted hemorrhagic lesions in the fundus of the glandular stomach, accompanied by statistically increased 5-bromo-2'-deoxyuridine (BrdU) labeling index in the fundic and pyloric regions. Furthermore, biochemical analysis demonstrated an increased activity of ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SAT), known as key late-limiting enzymes of the polyamine pathway, in the gastric fundus. The stress may induce a remarkable increase in expression of c-fos, c-jun and c-myc mRNAs in both fundic and pyloric regions of the glandular stomach. There were no remarkable changes in the esophagus. These results indicate that space restriction and water-immersion stress induced cell proliferation in the glandular stomach through overexpression of proto-oncogenes and increased ODC and SAT activities that might be related to the promotion of gastric carcinogenesis.
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PMID:Epithelial cell proliferation in the digestive tract induced by space restriction and water-immersion stress. 956 8

In this paper the authors examine current findings on the etiology of fibrous dysplasia. Particular emphasized is the role of the biochemical pathways and the genetic mutations occurring in the disease. In fact it is demonstrated that the McCune-Albright syndrome, a variant of fibrous dysplasia, is caused by the mutations of the GNAS 1 gene that codify for the alfa-subunit of the stimulatory guanine-nucleotide binding protein (G-protein). This mutation activates adenylate cyclase and consequently increases intracellular concentrations of cAMP. The increased signaling through the cAMP is believed to be responsible for the clinical characteristic of the McCune-Albright syndrome. The cap is translocated to the nucleus where a family of transcription factors is phosphorylated. This group of factors regulates the expression of CAp responsive genes: one of them, the c-fos proto-oncogene, produces a nuclear protein that binds with other proteins encoded by c-jun proto-oncogene, to form a transcription factor, AP-1. Several studies have shown an increase of c-fos mRNA in the bone lesions of patients with fibrous dysplasia. It suggests that the overexpression of c-fos may represent the first step in the carcinogenesis of bone sarcomas. Finally, attention is focused on the intravenous use of pamidronate as medical management in the treatment of the lesions that are not susceptible to surgical treatment.
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PMID:[Fibrous dysplasia. The clinico-therapeutic picture and new data on its etiology. A review of the literature]. 957 46

We reported the inhibitory effects of genistein, an inhibitor of tyrosine protein kinase (TPK), on ultraviolet B (UVB)-induced expression of c-fos and c-jun in SENCAR mouse skin. UVB irradiation substantially increased transcript levels of c-fos and c-jun mRNA in mouse skin. Topical application of genistein 60 min before UVB radiation reduced c-fos and c-jun expression in the mouse skin in dose-dependent manner. Inhibition was more pronounced in skin exposed to the low dose (5 kJ/m2) than to the high dose (15 kJ/m2) of UVB radiation. In addition, genistein exhibited more inhibition of c-fos than that of c-jun. Post-application of genistein after UVB exposure down-regulated the expressions of c-fos and c-jun, but to a lesser extent compared with pre-application. A431 human epidermoid carcinoma cells, which excessively express epidermal growth factor receptors (EGF-R), were used to investigate the possible mechanism of genistein's action. The results showed that genistein down-regulated the UVB-mediated phosphorylation of TPK-dependent EGF-R in a dose-dependent manner. We concluded that inhibition of UVB-induced c-fos and c-jun expression in mouse skin by genistein may, at least in part, result from the inhibition of TPK activities and down-regulation of EGF-R phosphorylation. Suppression of UVB-induced proto-oncogene expression in mouse skin suggests that genistein may serve as a potential preventative agent against photodamage and photocarcinogenesis.
Carcinogenesis 1998 Apr
PMID:Inhibition of ultraviolet B (UVB)-induced c-fos and c-jun expression in vivo by a tyrosine kinase inhibitor genistein. 960 Mar 50

Mainstream cigarette smoke (CS) trapped in phosphate-buffered saline solutions (smoke-bubbled PBS) has been shown to induce a strong stress response in cultured cells. This is reflected, for example, by the expression of stress genes such as c-fos and haem oxygenase, a transient decrease in the translation efficiency and the induction of cell cycle arrest. In these studies, peroxynitrite, the reaction product of nitric oxide (NO) and superoxide (O2-.), was identified as an active principle formed by CS in aqueous solutions. In the present study, we show that the CS-induced stress response is critically dependent on the intracellular glutathione (GSH) content which itself becomes diminished in cells exposed to smoke-bubbled PBS. Investigations using c-fos expression as a measure for cellular stress revealed a direct correlation between the smoke-bubbled PBS concentration necessary for stress-dependent c-fos expression and the intracellular GSH concentration observed in different cell lines. Correspondingly, 3T3 fibroblasts artificially depleted of GSH by pretreatment with buthionine-sulphoximine (BSO), an inhibitor of GSH synthesis, require significantly lower amounts of smoke-bubbled PBS to obtain a detectable c-fos expression, whereas, supplementation of the medium with N-acetyl-cysteine is an efficient treatment for the inhibition of a CS-induced c-fos response. We also show that the smoke-bubbled PBS-dependent loss of intracellular GSH is mainly attributable to the aldehyde fraction of CS, although these aldehydes by themselves cannot induce c-fos in these cells. The smoke-bubbled PBS-dependent c-fos response can, however, be mimicked when peroxynitrite and CS-related aldehydes, at the concentrations calculated to appear in smoke-bubbled PBS, are used in combination for cell exposure. Taken together, these results suggest that in cells exposed to aqueous extracts of CS, smoke-related aldehydes decrease the intracellular GSH content significantly, allowing peroxynitrite to interfere with specific target molecules resulting in the stress-specific expression of c-fos.
Carcinogenesis 1998 May
PMID:The cellular stress response induced by aqueous extracts of cigarette smoke is critically dependent on the intracellular glutathione concentration. 963 65

This study used the induction of squamous cell carcinomas on mouse skin as an experimental model to evaluate molecular and biochemical changes that contribute to the neoplastic phenotype. The study was facilitated by the development of keratinocyte cell culture assays that reproduce each stage of the carcinogenesis process, by discoveries of stage-specific genetic and epigenetic changes and by application of pharmacological and molecular tools that modify each step. An early event in the transformation of keratinocytes involves mutation and activation of the rasHa gene, producing a benign tumor. The phenotypic consequences of ras mutations are mediated by activation of the epidermal growth factor receptor (EGFR), upregulation of protein kinase C (PKC) alpha and AP-1 mediated transcriptional activity and inactivation of PKC delta through tyrosine phosphorylation. These changes in benign tumors are manifested by hyperproliferation (EGFR), aberrant expression of keratinocyte genes (PKC alpha and AP-1) and delayed terminal differentiation (PKC delta). Accumulated chromosomal abnormalities, multifocal phenotypic changes and alterations in gene expression are associated with premalignant progression. Upregulation of the fos gene and AP-1 transcriptional activity causes malignant conversion of benign keratinocytes. In the absence of c-fos, benign tumor cells fail to upregulate secreted angiogenic and proteolytic factors and this may prevent malignant conversion. These pathways provide targets for preventive strategies to interrupt the process of carcinogenesis prior to the evolution of the fully malignant tumor.
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PMID:The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis. 965 22

Erionite, a naturally occurring fibrous zeolite, is associated with the development of nonmalignant and malignant lung diseases and is more carcinogenic than asbestos fibers in man and rodent inhalation models of disease. To investigate the possible molecular mechanisms of erionite-induced toxicity and carcinogenesis and whether cationic content of erionite fibers was important, we examined c-fos and c-jun mRNA levels, activator protein-1 (AP-1) binding to DNA, and changes in cell proliferation and apoptosis in rat pleural mesothelial (RPM) cells exposed to different cation-substituted erionite fibers or crocidolite asbestos at various concentrations (1, 5, or 10 microg/cm2 dish) at time periods from 8 to 48 h after addition of minerals. c-fos mRNA levels in cells exposed to equal weight concentrations of various erionites and crocidolite fibers were increased comparably. When compared to other fibers, Na-erionite caused significantly increased levels of c-jun mRNA at lower mass concentrations (1 and 5 microg/cm2) than crocidolite asbestos, but comparable AP-1 binding to DNA. In comparison to untreated controls, numbers of RPM cells incorporating 5'-bromodeoxyuridine (BrdU) were increased dramatically after exposure to asbestos or Na-erionite at 5 and 10 microg/cm2. Significant dose-dependent increases in apoptosis were observed with asbestos at all time points, whereas erionites failed to induce apoptosis at 8 or 24 h, with minimal induction at higher concentrations than asbestos at 48 h. These data suggest that erionite increases the balance between cell proliferation (and/or abnormal DNA repair) and apoptosis, a normal mechanism of elimination of transformed or proliferating cells.
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PMID:Patterns of c-fos and c-jun proto-oncogene expression, apoptosis, and proliferation in rat pleural mesothelial cells exposed to erionite or asbestos fibers. 970 90

The E6 and E7 genes of HPV-16 or HPV-18 both are necessary for effective immortalization of primary human genital keratinocytes. To analyse the individual role of E6 and E7 genes in dysregulating cell growth, we cloned the HPV-16 E6, E7 and E6/E7 genes into retroviruses. Primary human keratinocytes (PHK) were then infected with these retroviruses and selected in differentiation-inducing medium (high calcium and serum). The E6/E7 retroviruses were the most effective at inducing differentiation-resistant colonies. Intermediate numbers of colonies were induced by E6 and low numbers by E7. Interestingly, only cultures infected with E7 and E6/E7 retroviruses showed a significant proportion of cells progressing into the S phase, consistent with our earlier studies showing that E7 is required for the efficient immortalization of genital keratinocytes. Accompanying this entry into S phase, the E7 or E6/E7 transduced cells expressed high levels of cyclins A, B and E, but lower levels of cyclin D. In addition, cdc-2, cdk-2 and cdk-4 were also increased. No significant differences were detected in the expression of c-myc and c-fos between the vector and any of the transduced cells. Keratinocytes infected with the E7 retrovirus exhibited decreased levels of Rb protein and increased levels of p53, whereas cells infected with E6-expressing retroviruses displayed normal levels of Rb protein and decreased levels of p53. Finally, E7 induced a three-fold increase in bcl-2 expression. Our results indicate that the HPV-16 E7 gene alone is sufficient to bypass keratinoctye growth arrest induced by serum and calcium exposure and that the discordant expression of several cell regulatory proteins accompanies this unregulated proliferation.
Carcinogenesis 1998 Aug
PMID:HPV-16 E7 protein bypasses keratinocyte growth inhibition by serum and calcium. 974 46

The mammary gland seems to be the only organ that is not fully developed at birth. Estrogens stimulate breast tissue via estrogen receptors (ERs). In the mammary gland, ER-mediated mechanisms have been shown to regulate: various growth factors, such as TGF-alpha and TGF-beta; enzymes, such as cathepsin D and plasminogen-activator; proto-oncogenes, such as c-fos, c-myc and HER-2/neu; cyclines and other regulatory substances that provide signaling systems for cell division and differentiation; other steroid receptors and epidermal growth factor receptors. Estrogen target genes contain estrogen-responsive elements. In these genes, transcription will be activated through interaction with the estrogen/ER protein complex. Subsequent activation of proto-oncogenes provides an explanation for the stimulating effect of estrogens on the glandular breast. Progesterone may be the key in influencing the risk of breast cancer with the peak of mitotic activity in the breast during the luteal phase of the menstrual cycle. On the other hand, in human breast cancer cell lines, both proliferation and inhibition have been observed with various progestational agents. Relevant biological and clinical issues are pregnancy and exposure to exogenous hormones. The intense hormonal stimulation of pregnancy (both estrogen and progesterone) has no adverse impact on the course of breast cancer. Pregnancy, with its mammogenetic differentiation, results in the protection of this organ from carcinogenesis. Characterization of specific lobular morphology serves as an indicator of the level of differentiation achieved by the organ, and thus provides means to assess the risk of the gland undergoing neoplastic transformation when exposed to given agents. Sufficient evidence exists to indicate the possibility of a slightly increased risk of breast cancer after approximately one decade of postmenopausal estrogen use. A review of the epidemiologic studies of postmenopausal hormone replacement and the risk of breast cancer fails to provide definitive evidence. Recent information derives from observations of cellular proliferation, plasma and tissue estradiol and progesterone receptor levels, and the percentage of apoptotic epithelial cells in human breast tissue. Several studies suggest that short-term, continuous combined HRT does not increase breast cancer recurrence or mortality. The participation of sexual hormones in the mammogenetic process during pregnancy might serve as an intermediate end point in assessing the effectiveness of hormones as chemopreventive agents. Investigations based on history, and breast morphology, should enable us to select estrogens and progestogens for HRT, and adopt optimal therapeutic regimens.
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PMID:Potential benefits of estrogens and progestogens on breast cancer. 992 May 36

Reactive oxygen species, including H2O2, play an important role in the tumor promotion process. Using an in vitro model of tumor promotion involving the rat liver epithelial oval cell line T51B, the tumor promoting activity of H2O2 in N-methyl-N'-nitro-N-nitrosoguanidine-initiated cells was studied. In this assay system, the promoting effect of H2O2 is evidenced by the formation of colonies in soft agar, appearance of foci in monolayer culture, disruption of gap junction communication (GJC) in foci areas and growth at higher saturation densities. H2O2 preferentially induced the expression of c-fos, c-jun, c-myc and egr-1, while JunB and JunD levels remained almost unchanged. H2O2 also induced hyperphosphorylation of Cx43 and disruption of GJC. The effects of H2O2 on tumor promotion, induction of immediate early (IE) genes and disruption of GJC are blocked by antioxidants. These results suggest that H2O2 acts as a tumor promoter in rat liver non-neoplastic epithelial cells and that the induction of IE genes and disruption of GJC are two possible targets of H2O2 during the tumor promotion process.
Carcinogenesis 1999 Mar
PMID:Tumor promotion by hydrogen peroxide in rat liver epithelial cells. 1019 May 66


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