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)

This study was designed to test the hypothesis that cyclin D1 overexpression is involved in the multistep process of gallbladder carcinogenesis and can be used to predict poor prognosis for patients with gallbladder carcinoma (GBC). Cyclin D1 expression was examined immunohistochemically in a series of specimens, including 8 normal epithelia, 8 benign adenomyoma lesions, 6 precancerous adenomas, and 37 carcinomas of the gallbladder. Four of the 6 (67%) adenomas and 15 of the 37 (41%) adenocarcinomas demonstrated cyclin D1 overexpression (>5% nuclear staining), whereas all normal epithelia and adenomyoma lesions were negative for cyclin D1. Kaplan-Meier curves showed that cyclin D1 overexpression was significantly related to decreased overall survival (P < 0.05) in patients with GBCs. The Cox proportional hazards model identified cyclin D1 overexpression as an independent prognostic marker for death (P = 0.024; risk ratio, 4.2; 95% confidence interval, 1.2-14.7). To test whether cyclin D1 overexpression is a critical event in gallbladder neoplasms, cyclin-dependent kinase inhibitor p27Kip1 was introduced to ascertain how cyclin D1 affects clinical outcomes. Subsequently, neoplasms were divided into three groups on the basis of the combination of cyclin D1 expression and p27Kip1 status, which had been determined previously. Group 1 showed no abnormality in either cyclin D1 or p27Kip1 expression. Group 2 showed aberrant expression of one of the two proteins, whereas group 3 showed concurrent abnormalities in both proteins. Results indicated that overall survival was greatest in group 1, followed by a significant decrease in group 2 and a more precipitous decrease in group 3. In conclusion, cyclin D1 overexpression is an early event in gallbladder carcinogenesis and independently predicts decreased survival for patients with GBC.
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PMID:Cyclin D1 overexpression is a critical event in gallbladder carcinogenesis and independently predicts decreased survival for patients with gallbladder carcinoma. 1110 43

There is strong evidence that estrogens are involved in the etiology, promotion and progression of a variety of cancers, including the cancers of the breast and endometrium. The Syrian hamster estrogen-induced, estrogen-dependent renal neoplasm is a well-established animal model used to elucidate the cellular and molecular mechanisms involved in solely estrogen-induced carcinogenic processes. G(1) cell cycle progression was studied in estrogen-induced early renal tumor foci and in large kidney tumors of castrated male hamsters. Levels of cyclin D1, cyclin E and retinoblastoma (pRb) proteins were higher in these renal neoplasias than in adjacent uninvolved renal tissue and kidneys from untreated, age-matched animals. Of particular interest is the presence of a predominant 35 kDa cyclin E protein variant form in primary renal tumors. In addition, amounts of the phosphorylated forms of cyclin-dependent kinases (cdk) 2 and 4 were decreased, and both RNA and protein levels of p27(kip1) (p27), a cyclin-dependent kinase inhibitor, were markedly higher in early and frank renal tumors than in adjacent uninvolved renal tissue and kidneys of untreated, age-matched animals. These changes in cell cycle components coincided with a rise in renal tumor cell proliferation. Binding of the elevated p27 protein to cyclin E, cdk2 and cdk4, however, was not impaired, suggesting that this cell cycle suppressor protein is functional. In addition, cyclin D1-, cdk2-, cdk4- and cyclin E-associated kinase activities were also lower in these estrogen-induced renal neoplasms than in untreated, age-matched kidneys. Interestingly, when compared with untreated kidney tissue, early and frank renal neoplasms had less of the 62 kDa native form of E2F1 and contained a 57 kDa variant form. Thus we have characterized an unusual deregulation of the cell cycle during estrogen-induced renal tumorigenesis in Syrian hamsters which still allows for estrogen-driven kidney tumor cell proliferation and may contribute to the early genomic instability found.
Carcinogenesis 2000 Dec
PMID:Unusual deregulation of cell cycle components in early and frank estrogen-induced renal neoplasias in the Syrian hamster. 1113 5

Epidemiological evidence suggests tea (Camellia sinensis L.) has chemopreventive effects against various tumors. Green tea contains many polyphenols, including epigallocatechin-3 gallate (EGCG), which possess anti-oxidant qualities. Reduction of chemically induced mammary gland carcinogenesis by green tea in a carcinogen-induced rat model has been suggested previously, but the results reported were not statistically significant. Here we have tested the effects of green tea on mammary tumorigenesis using the 7,12-dimethylbenz(a)anthracene (DMBA) Sprague-Dawley (S-D) rat model. We report that green tea significantly increased mean latency to first tumor, and reduced tumor burden and number of invasive tumors per tumor-bearing animal; although, it did not affect tumor number in the female rats. Furthermore, we show that proliferation and/or viability of cultured Hs578T and MDA-MB-231 estrogen receptor-negative breast cancer cell lines was reduced by EGCG treatment. Similar negative effects on proliferation were observed with the DMBA-transformed D3-1 cell line. Growth inhibition of Hs578T cells correlated with induction of p27(Kip1) cyclin-dependent kinase inhibitor (CKI) expression. Hs578T cells expressing elevated levels of p27(Kip1) protein due to stable ectopic expression displayed increased G1 arrest. Thus, green tea had significant chemopreventive effects on carcinogen-induced mammary tumorigenesis in female S-D rats. In culture, inhibition of human breast cancer cell proliferation by EGCG was mediated in part via induction of the p27(Kip1) CKI.
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PMID:Green tea extracts decrease carcinogen-induced mammary tumor burden in rats and rate of breast cancer cell proliferation in culture. 1150 Sep 15

Retinoids are essential for normal epidermal differentiation and are used for the prevention and treatment of numerous skin disorders and cancers in humans. In previous studies, we have shown that retinoic acid receptors (RARs) -alpha and -gamma are down-regulated during skin tumor progression. The transduction of v-ras(Ha) into primary mouse keratinocytes is sufficient to reduce both RARalpha and RARgamma protein levels as well as inhibit their transactivation functions. Our primary objective is to investigate the roles that RARalpha and RARgamma play in keratinocyte tumor cell proliferation. Through retroviral gene transduction, we overexpressed RARalpha or RARgamma into neoplastic mouse epidermal cells with down-regulated endogenous RAR proteins. Following all-trans retinoic acid (RA) treatment, RARalpha- and RARgamma-transduced cell lines exhibit a progressive, dose-dependent growth inhibition relative to the control LXSN cell lines. Further characterization of RAR-transduced cells following RA treatment reveals that both RARalpha and RARgamma cause a decrease in S-phase population, while only RARalpha causes a simultaneous G(0)/G(1) block as evidenced by reduced [(3)H]-thymidine incorporation and flow cytometric analysis of DNA content. Following RA treatment, both receptors cause an early, transient increase in the cyclin-dependent kinase inhibitor (CDKI) p21 proteins, while only RARalpha causes a simultaneous sharp, brief increase in the CDKI p16 protein. A later decrease in cyclin D(1) protein is also evident in RARalpha- and RARgamma-transduced cells. Chromatin condensation and PARP cleavage are observed in both RARalpha- and RARgamma-transduced cells indicating an RA-induced apoptosis that may be caspase dependent. Furthermore, both receptors cause a late upregulation and apparent cleavage of the squamous differentiation marker protein kinase C (PKC)-eta. These results suggest that RARalpha and RARgamma enhance growth suppression and apoptosis of neoplastic epidermal keratinocytes. This growth inhibitory effect of both retinoid receptors in neoplastic keratinocytes may be achieved through distinct as well as overlapping mechanisms of cell cycle control.
Carcinogenesis 2001 Dec
PMID:Overexpression of retinoic acid receptors alpha and gamma into neoplastic epidermal cells causes retinoic acid-induced growth arrest and apoptosis. 1175 25

The effect of some flavonoids, which are components of fruits, vegetables, and peas, on the cell cycle progression of human LNCaP prostate cancer cells has been investigated in this study. Genistein arrested the cell cycle at the G2/M phases, which is attributed to the suppression of cyclin B expression. In addition, genistein induced the cyclin-dependent kinase inhibitor p21, which does not depend on p53 activation. Apigenin and luteolin also increased p21 levels, but quercetin did not. Apigenin induced p21 production through a p53-dependent pathway, but luteolin did so in a p53-independent manner. These results suggest that flavonoids are potent regulators of cyclin B and p21 for cell cycle progression, which may play some roles in prevention of carcinogenesis.
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PMID:Effect of flavonoids on cell cycle progression in prostate cancer cells. 1179 Apr 49

p53 is a transcription factor for Waf-1/p21, a cyclin-dependent kinase inhibitor. Certain polymorphic variants of Waf-1 and p53 have been evaluated for their association with cancer risk. Previous studies indicated that certain p53 polymorphisms confer an increased risk of breast cancer [odds ratios (ORs) and 95% confidence intervals (CIs) = 2.9, 1.4-6.3 Carcinogenesis (Lond.), 17: 1313, 1996; 2.5, 1.3-4.8 Cancer Epidemiol. Biomark. Prev., 6: 105, 1997; and 1.5, 1.1-2.0, Anticancer Res., 18: 2095, 1998). The primary objectives of this study were to test the hypotheses that the serine variant (codon 31 polymorphism) of Waf-1 is also involved in this process and that there is an interaction between Waf-1 and p53 polymorphisms. To do this, Waf-1 and p53 genotypes were determined for women enrolled in a breast cancer case-control study (Caucasians, African-Americans and Latinas; 487 Waf-1 and 504 p53 genotypes were obtained). Multivariate logistic regression was used to evaluate possible associations between Waf-1 and p53 polymorphisms, race, and menopause. The primary aim was to determine whether an interaction between Waf-1 and p53(1-2-1) existed. Whereas multivariate analysis suggested associations between breast cancer and inheritance of Waf-1(ser31) in African-Americans (OR, 2.32; 95% CI = 0.66-5.60; n = 37 cases and 65 controls) and Latinas (OR, 2.22; 95% CI = 0.71-6.89; n = 30 cases and 75 controls), and inheritance of p53(1-2-1) in Caucasians (OR, 3.15; 95% CI = 1.14-8.89; n = 93 cases and 187 controls), we did not see an interaction between Waf-1(ser31) and p53(1-2-1). Consistent with the finding that p53(1-2-1) is a risk factor for Caucasian women was the observation of a strong interaction between race and p53 (P < 0.01).
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PMID:Waf-1 (p21) and p53 polymorphisms in breast cancer. 1181 10

The CDKN2 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor, p16, which regulates retinoblastoma protein (pRb)-dependent G1 arrest, and a cell cycle inhibitor, p14ARF, which blocks MDM2-induced p53 degradation resulting in an increase in p53 levels that leads to cell cycle arrest. Recent studies have revealed that expression of p16 and p14ARF is influenced markedly by the status of pRb and p53, and p16 overexpression has been demonstrated in cervical neoplasia because of functional inactivation of pRb by the human papillomavirus (HPV) E7 protein. To clarify the p14ARF status and the relationship between p16/p14ARF and other cell cycle molecules in cervical carcinogenesis, immunohistochemical analysis of p16, p14ARF, p53 and MDM2 was performed on 65 samples of cervical and genital condylomatous and neoplastic lesions, including nine HPV-negative tumors. In most cervical cancers and preneoplastic lesions with HPV infection of high and intermediate risk, a marked overexpression of p14ARF as well as the p16 protein (i.e. dotted nuclear immunostaining) was observed. All condyloma acuminata except one and low-grade dysplasia with HPV infection of low risk, such as HPV 6, immunohistochemically showed completely negative staining for p14ARF, also seen in non-neoplastic and mesenchymal cells. Our results clearly show that the mode of p14ARF overexpression in cervical neoplastic cells with HPV association differs from that in cancers of other organs without HPV association, and the p14ARF overexpression may be attributable to a negative feedback result in the functional inactivation of the pRb and p53 proteins by HPV oncoproteins.
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PMID:Overexpression of p16 and p14ARF is associated with human papillomavirus infection in cervical squamous cell carcinoma and dysplasia. 1210 May 20

The arylhydrocarbon receptor (AhR) was initially identified as a member of the adaptive metabolic and toxic response pathway to polycyclic aromatic hydrocarbons and to halogenated dibenzo-p-dioxins and dibenzofurans. In the present study, we sought to determine the functional significance of the AhR pathway in pancreatic carcinogenesis. AhR expression was analysed by Northern blotting. The exact site of AhR expression was analysed by in situ hybridization and immunohistochemistry. The effects of TCDD and four selective AhR agonists on pancreatic cancer cell lines were investigated by growth assays, apoptosis assays, and induction of the cyclin-dependent kinase inhibitor p21. There was strong AhR mRNA expression in 14 out of 15 pancreatic cancer samples, weak expression in chronic pancreatitis tissues, and faint expression in all normal pancreata. In pancreatic cancer tissues, AhR mRNA and protein expression were localized in the cytoplasm of pancreatic cancer cells. TCDD and the four AhR agonists inhibited pancreatic cancer cell growth in a dose-dependent manner, and decreased anchorage-independent cell growth. DAPI staining did not reveal nuclear fragmentation and CYP1A1 and was not induced by TCDD and AhR agonists. In contrast, TCDD and AhR agonists induced the expression of the cyclin-dependent kinase inhibitor p21. In conclusion, the relatively non-toxic AhR agonists caused growth inhibition in pancreatic cancer cells with high AhR expression levels via cell cycle arrest. In addition, almost all human pancreatic cancer tissues expressed this receptor at high levels, suggesting that these or related compounds may play a role in the therapy of pancreatic cancer in the future.
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PMID:Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer. 1220 18

As a broad-acting cyclin-dependent kinase inhibitor, p21(WAF1) occupies a central position in the cell cycle regulation of self-renewing tissues such as oral mucosa and skin. In addition to regulating normal cell cycle progression decisions, p21(WAF1) integrates genotoxic insults into growth arrest and apoptotic signaling pathways that ultimately determine cell fate. As a result of its complex interactions with cell cycle machinery and response to mutagenic agents, p21(WAF1) also has stage-specific roles in epithelial carcinogenesis. Finally, a view is emerging of p21(WAF1) as not merely a cyclin-dependent kinase inhibitor, but also as a direct participant in regulating genes involved in growth arrest, senescence, and aging, thus providing an additional layer of control over matters of the cell cycle. This review discusses these various roles played by p21(WAF1) in cell cycle control, and attempts to relate these to epithelial cell biology, with special emphasis on keratinocytes.
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PMID:P21Waf1 control of epithelial cell cycle and cell fate. 1249 39

Phospholipase D (PLD) is known to stimulate cell cycle progression and to transform murine fibroblast cells into tumorigenic forms, although the precise mechanisms are not elucidated. In this report, we demonstrated that both PLD1 and PLD2 repressed expression of cyclin-dependent kinase inhibitor p21 gene in an additive manner. The phospholipase activity of PLDs was important for the effect. PLD1 repressed the p21 promoter by decreasing the level of p53, whereas PLD2 via a p53-independent pathway through modulating Sp1 activity. Taken together, we suggest that PLD isozymes stimulate cell growth by repressing expression of p21 gene, which may ultimately lead to carcinogenesis.
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PMID:Transcriptional repression of cyclin-dependent kinase inhibitor p21 gene by phospholipase D1 and D2. 1278 87


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