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)

Cyclin D1 overexpression is remarkably frequent in several human carcinomas and is believed to be a critical event in oncogenesis. We examined cyclin D1 expression, p53 expression, and the Ki-67 labeling index by immunostaining in human gallbladder mucosa in conditions varying from normal to malignant tissue. We also examined K-ras codon 12 mutations in these tissues with a two-step polymerase chain reaction. Nuclear cyclin D1 overexpression was observed in 48% of carcinomas occurring independently of adenoma, but not in adenomas, carcinomas arising in adenomas, or nonneoplastic lesions. Cytoplasmic cyclin D1 overexpression was observed in about 15% of abnormal specimens, irrespective of the type of epithelial abnormality. Carcinomas showing nuclear cyclin D1 overexpression had significantly higher Ki-67 labeling indexes than those with no overexpression. Moderately to poorly differentiated adenocarcinomas showed a higher incidence of nuclear cyclin D1 overexpression than papillary to well differentiated carcinomas. Specimens with cyclin D1 overexpression showed a high incidence of lymph permeation, venous permeation, and lymph node metastasis. We conclude that nuclear cyclin D1 overexpression is a critical event importantly associated with cell proliferation and invasive growth in gallbladder carcinogenesis, and that cyclin D1 immunostaining may become a useful marker for evaluating gallbladder carcinomas.
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PMID:Nuclear cyclin D1 overexpression is a critical event associated with cell proliferation and invasive growth in gallbladder carcinogenesis. 1068 Jun 70

Effects of a genotoxic bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and a non-genotoxic bladder promoter, sodium L-ascorbate (Na-AsA), on protein expression, cell proliferation and apoptosis of the bladder epithelium with or without the influence of testicular castration were investigated. Male F344 rats were divided into six groups (groups 1-6). BBN was given with 0.05% drinking water to groups 1 and 4 for 8 weeks, groups 2 and 5 received diet with 5% Na-AsA. Then the animals were treated without any chemicals. Groups 3 and 6 were non-treated controls. Testicular castration was carried out 2 weeks before commencement of chemical treatment on groups 4-6. The total observation period was 18 weeks. Overexpression of cyclin D1 was induced by BBN but not Na-AsA and the degree of overexpression was higher in the order simple hyperplasia, papillary or nodular hyperplasia, papilloma and carcinoma. Metallothionein (MT) was also overexpressed in bladder epithelium treated with BBN but not Na-AsA, but was decreased in papillomas and never found in a carcinoma. Cyclin D1-positive cells were essentially MT-negative. Therefore, it is speculated that MT protects genes from insult by genotoxic carcinogens and its lack is associated with tumor development. Apoptotic cell death occurred during treatment with BBN and Na-AsA and after their withdrawal. Chromatin condensation of many G0/G(1) cells was particularly marked on flow cytometry analysis 1 week after cessation of treatment, this being considered as an early apoptotic change. Although testicular castration had no influence on the above events, it resulted in decreased tumor formation as compared with the case of similarly treated intact animals. Our data demonstrate that overexpression of MT and cyclin D1 is specific for treatment with a genotoxic carcinogen, and suggest that MT overexpression may play an important suppressive role in the early stages of rat urinary bladder carcinogenesis.
Carcinogenesis 2000 Apr
PMID:Significant overexpression of metallothionein and cyclin D1 and apoptosis in the early process of rat urinary bladder carcinogenesis induced by treatment with N-butyl-N-(4-hydroxybutyl)nitrosamine or sodium L-ascorbate. 1075 5

The cell cycle regulatory gene, Cyclin D1, plays a critical role in the growth and progression of several types of human cancer, including breast cancer. Immunohistochemical study of Cyclin D1 expression has been extensively reported in invasive ductal carcinoma (IDC). In contrast, there have been few reports concerning Cyclin D1 expression in ductal carcinoma in situ (DCIS) and their positive rates are variable. The differences in the reported frequency may be largely due to the differences in antibodies used, immunohistochemical methods and the positive cut-off point. However, we speculated that the strictness of diagnosis of DCIS might be somewhat responsible for these differences in frequency. Therefore, we selected cases of DCIS by carefully eliminating cases of predominantly intraductal carcinoma (PIC). Moreover, to clarify whether Cyclin D1 expression is involved in multistep carcinogenesis or the progression of human breast cancer, we immunohistochemically investigated Cyclin D1 expression in 57 DCIS, 10 atypical ductal hyperplasia (ADH), 70 usual ductal hyperplasia (UDH), 44 PIC and 92 IDC. Cyclin D1 expression was detected in 41 DCIS cases (72%), 22 PIC cases (50%) and 40 IDC cases (43%). No expression of Cyclin D1 was observed in either ADH or UDH. There were no significant correlations between Cyclin D1 expression and histological grade or estrogen receptor expression in DCIS. These results suggest that Cyclin D1 expression may play an important role in the early stages of carcinogenesis, and that immunohistochemical detection of Cyclin D1 expression may be helpful in differentiating low-grade DCIS from ADH.
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PMID:Cyclin D1 expression in ductal carcinoma in situ, atypical ductal hyperplasia and usual ductal hyperplasia: an immunohistochemical study. 1088 33

Hepatocytes are capable of marked changes in proliferation in response to various physiological and pathophysiological stimuli. Although the changes in adult hepatocyte growth regulation that accompany reduction of liver mass, liver injury, and liver carcinogenesis have come under intense scrutiny, the regulation of hepatocyte growth during the latter stages of development is largely uncharacterized. We have examined hepatic cell cycle control in the developing rat. Analysis of term (fetal day 21) liver and cultured, term hepatocytes revealed G0-G1 growth-arrested cells relative to preterm (fetal day 19) liver and isolated hepatocytes. G1 cyclin-dependent kinase (CDK) activity was correlated with growth arrest at term in both in vivo and in vitro studies. The decline in CDK activity at term could not be attributed to a change in CDK protein content. Rather, the decline in CDK activity was associated with a concomitant decline in cyclin D1 protein content. However, cyclin D1 mRNA levels did not correlate with protein levels. Cyclin D1 mRNA was present at a higher level in adult livers, in which cyclin D1 protein was absent, than in fetal livers. We also examined the phosphorylation (activation) state of p38 mitogen-activated protein kinase, a potential hepatocyte-growth regulator and modulator of cyclin D1 content. p38 activity was inversely related to cyclin D1 content during liver development and regeneration. These data indicate that a posttranscriptional mechanism regulating cyclin D1 content is involved in the temporary hepatocyte growth arrest seen in the perinatal period and in the maintenance of adult hepatocytes in a quiescent state. We speculate that this posttranscriptional regulation may be downstream from the p38 mitogen-activated protein kinase pathway.
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PMID:Cell cycle control during liver development in the rat: evidence indicating a role for cyclin D1 posttranscriptional regulation. 1091 99

Cell cycle progression is facilitated by cyclin-dependent kinases that are activated by cyclins including cyclin D1 and inactivated by cyclin-dependent kinase inhibitors (CDKIs) such as p27. Our previous studies have demonstrated decreased p27 expression in both papillary and more aggressive carcinomas of the thyroid compared to thyroid adenoma and almost similar level of cyclin D1 expression between thyroid adenoma and papillary carcinoma. These results indicate that CDKIs may have an important role in the carcinogenesis of the thyroid and that they probably have a limited role in malignant progression of the thyroid cancer. The role of cyclin D1 in malignant progression of thyroid carcinoma has yet to be established. We studied the expression of cyclin D1 by immunohistochemistry in 34 cases of conventional papillary carcinoma (CPC), 10 cases of minimally invasive follicular carcinoma (MIFC), and 32 cases of more aggressive thyroid carcinoma (ATC), which included 11 tall cell variants, one columnar cell variant of papillary carcinoma, seven insular carcinomas, and 13 anaplastic carcinomas. Cyclin D1 staining was classified by staining score as 0, negative; 1+, less than 25%; 2+, 25 to 50%; and 3+, more than 50% tumor cells staining positive. Kruskal-Wallis one-way ANOVA and Wilcoxon Rank Sum/Mann-Whitney U Test was used to assess the difference in the expression of cyclin D1 between the study groups. Twenty-eight out of the 34 CPCs were cyclin D1 positive, 24 (70%) were 1+, 3 (9%) were 2+, and one (3%) were 3+ positive. Seven of 10 MIFCs were cyclin D1 positive, five (71%) were 1+, and the remaining two (29%) were 2+ positive. On the other hand, 28 of 32 ATCs showed cyclin D1 immunostaining. Of these, three (9%) were 1+, five (13%) were 2+, and 20 (63%) were 3+ positive. This study demonstrates a significant overexpression of cyclin D1 in ATC compared CPC (P < .001) and MIFC (P < .005), suggesting that the cyclin D1 expression may play a role in tumor progression and may have prognostic significance in thyroid cancer.
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PMID:The role of cell cycle regulatory protein, cyclin D1, in the progression of thyroid cancer. 1095 55

Cyclin D1 is a cell cycle regulatory protein, which acts as a growth factor sensor to integrate extracellular signals with the cell cycle machinery, particularly during G1 phase of the cell cycle. Previous study using promotion-sensitive JB6 mouse epidermal cells, an in vitro model of the promotion stage of multistage carcinogenesis, showed that the expression of cyclin D1 is stimulated in the presence (but not in the absence) of 12-O-tetradecanoylphorbol-13-acetate (TPA) in these cells maintained under anchorage-independent culture conditions. In the present study, to explore the molecular basis of this observation, the promoter region of mouse cyclin D1 gene was cloned and sequenced (GenBank accession number AF212040). Dot matrix comparison of mouse, human and rat promoter sequences indicated that the mouse promoter is homologous to the human and more so to the rat promoters. The mouse promoter, like human and rat promoters, lacks canonical TATA-box or TATA-like sequence, but it has one or possibly two initiator (Inr) or Inr-like sequences. Energy dot plot analysis predicted that the mouse promoter consists of three domains: (1) the 3' domain contains NF-kappaB response element, cAMP-response element (CRE), Inr or Inr-like elements, Sp1 binding site and Oct 1 (2) the middle domain contains another Sp1 binding site, E-box and E2F binding site and (3) the 5' domain contains TPA-response element (TRE) and a tandem silencer element. The cyclin D1 promoter sequence of either promotion-sensitive or resistant JB6 mouse epidermal cells was, except for a few minor differences, essentially identical to the sequence determined for a mouse genomic clone. Since TPA is capable of stimulating the expression of cyclin D1 not only through TRE but also through CRE and NF-kappaB response element in the promoter, we tentatively propose a sequence of events that possibly leads to TPA-induced, anchorage-independent synthesis of cyclins D1 and A in the promotion-sensitive JB6 mouse epidermal cells.
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PMID:Molecular cloning and sequence analysis of the promoter region of mouse cyclin D1 gene: implication in phorbol ester-induced tumour promotion. 1095 25

Cyclin D1, P53 and P21 (WAF1) are cell cycle regulating proteins, playing a crucial role in oncogenesis of a large number of human malignancies, and loss of activity of P53 and P21 (WAF1) proteins seems to be one of the most important regulatory mechanisms of carcinogenesis in colorectal cancer. To find out their mutual relations we investigated the expression of cyclin D1, P53 and P21 (WAF1) in 122 colorectal cancers by immunohistochemistry. Positivity for cyclin D1 was found in all the cases (100%), positivity for P53 in 96 cases (70%) and positivity for P21 in 48 cases (39%). Statistical analysis revealed a statistically significant inverse correlation between P53 and P21 (WAF1)-immunopositivity and also between P21 (WAF1)-immunopositivity and the degree of cyclin D1-immunopositivity. These data suggest that in colorectal cancer induction of P21 (WAF1) may occur mostly in a P53-dependent pathway. Wild-type P53, which is undetectable by immunohistochemistry, induces transcriptionally P21 (WAF1) and in tumours it may cause its accumulation, while mutations of the P53 may result in a sufficient increase of intracellular protein having no ability to transactivate P21 (WAF1). Moreover P21 (WAF1) as the main cyclin-dependent kinases (CDKs) inhibitor may also inhibit the activity of the cyclins, thus overexpression of P21 (WAF1) may result in reduced level of cyclin D1.
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PMID:Comparative evaluation of the expression of cell cycle regulating proteins: cyclin D1, P53 and P21 (WAF1) in colorectal cancer. 1097 28

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

Alterations in expression of the p53 and cyclin D1 genes have been implicated in the development of esophageal carcinomas in both humans and animal models. We hypothesize that altered expression of cyclin D1 and p53 may be involved in the sequential development of esophageal carcinomas with glandular differentiation induced by the carcinogen, 2,6-dimethylnitrosomorpholine (DMNM) in rats with duodenal content reflux esophagitis. In the present study Sprague-Dawley rats were given DMNM 15 days after performing an esophago-jejunostomy in order to induce chronic duodenal content reflux esophagitis. Expression and localization of p53, cyclin D1 and Ki-67 were examined by immunohistochemical analyses. Twenty of 24 animals developed different types of esophageal carcinomas, including pure squamous carcinoma, adenosquamous carcinoma and pure adenocarcinoma. Undifferentiated basaloid areas were frequently observed in these tumors. Cyclin D1 overexpression was observed in hyperplastic lesions and increased through dysplasia and in undifferentiated areas of infiltrating carcinoma. Cyclin D1 expression coincided with increased Ki-67 expression and decreased along with cell differentiation. The p53 immunohistochemical pattern was parallel to that of cyclin D1, although the percentage of positive cells was usually smaller in all lesions and increased p53 expression started at the dysplastic stage. These findings suggest that overexpression of cyclin D1 may be an early event in DMNM-induced rat esophageal tumorigenesis, causing increased proliferation of esophageal stem cells. Abnormal p53 expression may then be required to promote the development of neoplastic transformation from dysplastic epithelium through invasive phenotype, being more evident in cancer cells with squamous differentiation.
Carcinogenesis 2001 Feb
PMID:Expression of cyclin D1 and p53 and its correlation with proliferative activity in the spectrum of esophageal carcinomas induced after duodenal content reflux and 2,6-dimethylnitrosomorpholine administration in rats. 1118 48

Cyclin D1 is a known oncogene and a key regulator of cell cycle progression. Amplification of the cyclin D1 gene and its overexpression have been associated with aggressive forms of human hepatocellular carcinoma (HCC). In this study, two independent lines of transgenic mice have been generated that express cyclin D1 under the control of the rat liver fatty acid binding protein promoter. This transgene specifically directs expression in the liver and the intestines. RNA and protein analysis demonstrated increased expression of the cyclin D1 gene product in the liver and bowel when compared with wild-type siblings. Both transgenic lines developed progressive liver disease. Examination of H&E stained sections of the liver and bowel revealed hyperplastic changes in the liver by 3 months of age. By 6 months of age, transgenic mice had obvious hepatomegaly and histological evidence of dysplasia in the liver. These early changes were significantly more dramatic in male animals when compared with female animals. By 9 months of age adenomas of the liver appeared, progressing to HCC over the ensuing 6-month period. By 15-17 months of age, 87% of male and 69% of female animals had either adenomatous nodules or HCCs. By 17 months of age, 31% of male and female animals had disease that had progressed to HCC. These animals represent a unique and significant new model for the study of human HCC. This study demonstrates that overexpression of cyclin D1 is sufficient to initiate hepatocellular carcinogenesis.
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PMID:Hepatocellular carcinoma results from chronic cyclin D1 overexpression in transgenic mice. 1145 81


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