Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

High level of cyclin A promotes carcinogenesis, and overexpression of cyclin A has been associated with poor prognosis of cancer patients. We validated the prognostic role of cyclin A in gastric cancer and evaluated its correlation with expression of an mRNA stability factor HuR. From 342 consecutive histologically confirmed gastric cancer patients were obtained 325 representative tissue specimens for cyclin A and 316 for HuR immunohistochemistry. Specimens were stained by cyclin A and HuR specific monoclonal antibodies. Nuclear immunostaining detected in > or =5% of the tumor cells was considered the cut-off for cyclin A positivity. Positive HuR immunoreactivity was scored as nuclear or cytoplasmic. Associations between scores, clinicopathological factors and survival were calculated by the chi2-test, Fisher's exact test, Kaplan-Meier test and Cox model. Cyclin A detected in the nuclei of cancer cells was positive in 55% (179 of 325) of the specimens; 40% (127 of 316) of the specimens had cytoplasmic and 88% (279 of 316) nuclear immunoreactivity of HuR. Cyclin A expression was an independent prognostic factor for poor survival. Cyclin A immunoreactivity was associated with old age, high stage, proximal location of the tumor, intestinal type, noncurative resection, advanced penetration depth and with nodal metastases but not distant metastases. Furthermore, cyclin A expression was associated with cytoplasmic HuR expression, whereas no association with nuclear HuR was evident. Cyclin A is an independent prognostic factor in gastric cancer, and one mechanism for its overexpression may depend on cytoplasmic localization of HuR.
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PMID:Prognostic significance of cyclin A in gastric cancer. 1670 83

Fanconi anemia (FA) is a recessive disorder associated with progressive pancytopenia, multiple developmental defects, and marked predisposition to malignancies. FA is genetically heterogeneous, comprising at least 12 complementation groups (A-M). Activation of one of the FA proteins (FANCD2) by mono-ubiquitination is an essential step in DNA damage response. As FANCD2 interacts with BRCA1, is expressed in proliferating normal breast cells, and FANCD2 knockout mice develop breast tumors, we investigated the expression of FANCD2 in sporadic and hereditary invasive breast cancer patients to evaluate its possible role in breast carcinogenesis. Two tissue microarrays of 129 and 220 sporadic breast cancers and a tissue microarray containing 25 BRCA1 germline mutation-related invasive breast cancers were stained for FANCD2. Expression results were compared with several clinicopathological variables and tested for prognostic value. Eighteen of 96 (19%) sporadic breast cancers and two of 21 (10%) BRCA1-related breast cancers were completely FANCD2-negative, which, however, still showed proliferation. In the remaining cases, the percentage of FANCD2-expressing cells correlated strongly with mitotic index and percentage of cells positive for the proliferation markers Ki-67 and Cyclin A. In immunofluorescence double staining, coexpression of FANCD2 and Ki-67 was apparent. In survival analysis, high FANCD2 expression appeared to be prognostically unfavorable for overall survival (p = 0.03), independent from other major prognosticators (p = 0.026). In conclusion, FANCD2 expression is absent in 10-20% of sporadic and BRCA1-related breast cancers, indicating that somatic inactivating (epi)genetic events in FANCD2 may be important in both sporadic and hereditary breast carcinogenesis. FANCD2 is of independent prognostic value in sporadic breast cancer.
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PMID:Loss of expression of FANCD2 protein in sporadic and hereditary breast cancer. 1733 36

The aim of the research was to evaluate the expression levels of cyclin E/A and CDC25A/B during laryngeal carcinogenesis. The expression was demonstrated using immunohistochemistry in 46 cases of laryngeal cancer (LSCC), 23 epithelial dysplasias (ED) and 21 samples of normal mucosa (NM). The mean labeling indices (LI) for cyclin E in LSCC, ED and NM were 10.6, 4.9 and 0%; for cyclin A 27.2, 17.5 and 7%; for CDC25A 73.9, 53 and 32% and for CDC25B 36.5, 25.9 and 0%, respectively. A gradual increase in cyclin A and CDC25A expression levels from mild through moderate and severe dysplasia to in situ carcinoma were noted. Cyclin A LI significantly increased also from NM through ED to LSCC. Cyclin A and CDC25A LI significantly increased from NM to ED. Overexpression of cyclin A and CDC25A was significantly associated with proliferation among ED. Linear interdependency was detected in ED between the expression of CDC25A and cyclin A. Cyclin E and CDC25B overexpression occurs as a late event in neoplastic transformation. The progressive expression of proteins supports the multistep model of laryngealcarcinogenesis. The results indicate a possible role of cyclin A as a marker reflecting cell proliferation. The enhanced immunoexpression of cyclin A and CDC25A suggests the potential for malignant formation in preneoplastic lesions.
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PMID:Expression patterns of cyclin E, cyclin A and CDC25 phosphatases in laryngeal carcinogenesis. 1736 12

The purpose of this study was to investigate the chemopreventive effect of carotenoids on proliferating cell nuclear antigen (PCNA) and cyclin D(1) expression in betel (Areca catechu) quid extract (BQE)-induced hamster oral cancer and human KB cell models, respectively. In the in vivo animal study, 41 hamsters were divided into six groups and treated with 0.3 ml of 0.5% 9,10-dimethyl-1,2-benz[a]-anthracene, BQE, alpha-tocopherol, beta-carotene, lycopene, lutein and mixed carotenoids for 12 weeks. After treatment, the pouches were excised and graded using an immunohistochemical assay of PCNA. In the in vitro cell experiment, KB cells were cultured, and the inhibitory effect of carotenoids (beta-carotene, lycopene and lutein) on cell proliferation was evaluated. Cyclin D(1) and PCNA were evaluated in terms of cell differentiation. In the results, most of the animal lesions showed no overexpression of PCNA. However, in dysplastic lesions, PCNA expressions by the beta-carotene, lutein, lycopene, mixed and vitamin E groups were less than that of the control group. In papilloma lesions, PCNA expressions by the beta-carotene, mixed and vitamin E groups were less severe than that of the control group. PCNA expression by the vitamin E-treated group was less severe than that of the control group. No carcinoma was found in the lycopene or mixed groups. In the cell study, all carotenoids exerted a significant inhibitory effect on KB cell proliferation. Although lycopene suppressed KB cell proliferation at the G(0)/G(1) phase with a significant decrease in PCNA expression, beta-carotene and lutein possessed less of an inhibitory effect and even exhibited elevated cell proliferation at the G(2)/M phase. These results indicate that different carotenoids present various suppressive abilities against PCNA and cyclin D(1) expressions in cell proliferation. In conclusion, carotenoids suppressed the carcinogenesis of induced hamster oral cancer and a cancer cell line by acting as a suppressor which inhibited the expressions of PCNA and cyclin D(1).
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PMID:Carotenoids suppress proliferating cell nuclear antigen and cyclin D1 expression in oral carcinogenic models. 1736 34

The initiation of endoplasmic reticulum (ER) stress has been suggested to play potential roles in hepatocarcinogenesis. However, many obstacles remain as to whether ER stress plays a role in carcinogenesis or tumoricide. This study sought to identify the signals that can serve as anticancer effectors in cells in response to ER stress. Tunicamycin (an N-glycosylation inhibitor) inhibited cell proliferation with IC(50) values of 0.19 and 0.62 microg/ml in hepatoma (Hep) 3B and HepG2 cells, respectively. It induced G1 arrest of the cell cycle in both cell lines. The anticancer mechanism of tunicamycin was investigated in Hep3B cells. Tunicamycin induced a rapid decline of cyclin D1 and cyclin A expression and an early increase of glucose-related protein (GRP) 78 and growth arrest and DNA damage-inducible transcription factor (GADD) 153 levels. Cyclin A was the most sensitive regulator to tunicamycin-triggered degradation mechanism. The association of p27(Kip1) with cyclin D1/cyclin-dependent kinase (Cdk) 4 was also increased by tunicamycin. The inhibition of GADD153 expression by transfection of GADD153 antisense did not modify tunicamycin-induced G1 arrest and cyclin/Cdk expressions. The knockdown of GRP78 expression by the siRNA transfection technique moderately increased tunicamycin-induced apoptosis but not the antiproliferative effect by sulforhodamine B assay. We suggest that tunicamycin induces G1 arrest through down-regulation of cyclins and Cdks, in which cyclin A is more susceptible to ER stress-triggered degradation mechanism in Hep3B cells. The increased association of p27(Kip1) with cyclin D1/Cdk4 may also contribute to tunicamycin-induced cell-cycle arrest. GADD153 and GRP78 play a minor role in tunicamycin-mediated antiproliferative effect, although GRP78 moderately inhibits apoptosis in Hep3B cells. These data provide evidence that cell-cycle regulators are susceptible factors in hepatocellular carcinoma (HCC) responsive to ER stress.
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PMID:Elucidation of susceptible factors to endoplasmic reticulum stress-mediated anticancer activity in human hepatocellular carcinoma. 1822 3

Lung cancer is the most lethal carcinoma worldwide. Mutations of p53, inactivation of p16(INK4a), and overexpression of cyclins E, A and B are independently associated with poor prognoses of patients, while the prognostic value of cyclin D1 or RB expression is inconclusive. Cyclin D binding myb-like protein 1 (Dmp1) encodes a DNA binding protein that receives signals from oncogenic Ras and functions as a tumor suppressor by activating the Arf-p53 [corrected] pathway. Dmp1 has been shown to be haplo-insufficient for tumor suppression in mouse models including K-ras-mediated lung carcinogenesis. The human DMP1 gene is located on chromosome 7q21, and our recent results revealed that the hDMP1 gene is deleted, but not mutated or silenced, in approximately 40 % of human non-small-cell lung carcinomas. These cases typically retained wild-type ARF and p53 and expressed very low levels of the hDMP1 protein. Thus, hDMP1 loss could be a novel diagnostic marker for non-small-cell lung carcinomas.
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PMID:Role of DMP1 and its future in lung cancer diagnostics. 1859 25

The proteolytic destruction of cyclin B is an important event during cell division. Cyclin B proteolysis is triggered by the anaphase-promoting complex. Therefore, cell cycle dysregulation due to anaphase-promoting complex loss contributes to cell transformation and human carcinogenesis. This study investigates anaphase-promoting complex7 expression in spindle cell breast tumors and also includes a comparison between the proliferation antigen Ki-67 and S-phase fraction. The average values of the anaphase-promoting complex7 and Ki-67 labeling indices increased in order from benign to malignant within the phyllodes tumor group, and the fibroadenoma and juvenile fibroadenoma exhibited lower levels of anaphase-promoting complex7 and Ki-67 expression than did the phyllodes tumor. The frequency of anaphase-promoting complex7-positive stromal cells correlated with Ki-67 expression in phyllodes tumor and in all of the examined breast tumors. The above results indicate that anaphase-promoting complex7 and Ki-67 are closely related to cell proliferation. In addition, phyllodes tumor can be differentiated from juvenile fibroadenoma with increased mitotic figures mimicking phyllodes tumor by anaphase-promoting complex7 and Ki-67 immunochemistry. Because anaphase-promoting complex7 is expressed at higher levels than is Ki-67, it may overcome the limitations of the Ki-67 labeling index with regard to the differentiation of benign phyllodes tumor from fibroadenoma.
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PMID:Expression of anaphase-promoting complex7 in fibroadenomas and phyllodes tumors of breast. 1878 87

Cyclin D1b is an alternative transcript of the cyclin D1 gene (CCND1) expressed in human tumors. Its abundance is regulated by a single base pair polymorphism at the exon 4/intron 4 boundary (nucleotide 870). Epidemiological studies have shown a correlation between the presence of the G870A allele (that favors the splicing for cyclin D1b) with increased risk and less favorable outcome in several forms of cancer. More recently, it has been shown that, unlike cyclin D1a, the alternative transcript D1b by itself has the capacity to transform fibroblasts in vitro. In order to study the oncogenic potential of cyclin D1b, we developed transgenic mice expressing human cyclin D1b under the control of the bovine K5 promoter (K5D1b mice). Seven founders were obtained and none of them presented any significant phenotype or developed spontaneous tumors. Interestingly, K5D1b mice do not develop the fatal thymic hyperplasia, which is characteristic of the cyclin D1a transgenic mice (K5D1a). Susceptibility to skin carcinogenesis was tested in K5D1b mice using two-stage carcinogenesis protocols. In two independent experiments, K5D1b mice developed higher papilloma multiplicity as compared with wild-type littermates. However, when K5D1b mice were crossed with cyclin D1KO mice, the expression of cyclin D1b was unable to rescue the carcinogenesis-resistant phenotype of the cyclin D1 KO mice. To further explore the role of cyclin D1b in mouse models of carcinogenesis we carried out in silico analysis and in vitro experiments to evaluate the existence of a mouse homologous of the human cyclin D1b transcript. We were unable to find any evidence of an alternatively spliced transcript in mouse Ccnd1. These results show that human cyclin D1b has different biological functions than cyclin D1a and confirm its oncogenic properties.
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PMID:Enhanced skin carcinogenesis and lack of thymus hyperplasia in transgenic mice expressing human cyclin D1b (CCND1b). 1894 17

We aimed to evaluate the carcinogenesis risk in inflammatory bowel disease via p53 mutation and its relation with hyperproliferation (cyclin-D1) and angiogenesis (with vascular endothelial growth factor [VEGF] and microvessel density) and whether these events play important roles in pathogenesis of inflammatory bowel disease. Colonic tissue samples of 26 ulcerative colitis, 6 Crohn's disease, and 8 amoebic colitis patients as well as samples of 10 healthy controls were stained with p53, cyclin-D1, CD34, and VEGF monoclonal antibodies by immunohistochemistry and evaluated semiquantitatively. Expression of p53 was higher in ulcerative colitis than in the healthy control and amoebic colitis groups (4.15 +/- 2.07, 1.4 +/- 1.5, 1.3 +/- 1.5; P < 0.001). The Crohn's disease group had the highest p53 expression (4.6 +/- 1.6). The Crohn's disease, ulcerative colitis, and amoebic colitis groups all had higher VEGF expression than did the healthy controls (respectively, 4.3 +/- 1.2, 2.92 +/- 2.0, 2.3 +/- 1.5, 0.6 +/- 0.97; P < 0.001). Also, microvessel density was statistically higher in all three colitis groups than in healthy controls. Cyclin-D1 expression in all four groups was similar. The study showed that p53 mutation was present in nonneoplastic mucosa of inflammatory bowel disease patients. Detecting strong p53 overexpression with VEGF overexpression may help in differentiating inflammatory bowel disease from other colitis.
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PMID:Expression of p53, VEGF, microvessel density, and cyclin-D1 in noncancerous tissue of inflammatory bowel disease. 1903 59

Endometrial serous carcinomas (ESC) constitute only approximately 10% of endometrial cancers, but have a substantially higher case-fatality rate than their more common endometrioid counterparts. The precise composite of factors driving endometrial serous carcinogenesis and progression remain largely unknown, but we attempt to review the current state of knowledge in this report. ESC probably do not evolve through a single pathway, and their underlying molecular events probably occur early in their evolution. TP53 gene mutations occur in 22.7 to 96% of cases, and p53 protein overexpression is seen in approximately 76%. By gene expression profiling, p16 is upregulated in ESC significantly above both normal endometrial cells and endometrioid carcinomas, and 92-100% of cases display diffuse expression of the p16 protein by immunohistochemistry (IHC). Together, these findings suggest dysregulation of both the p16(INKA)/Cyclin D-CDK/pRb-E2F and the ARF-MDM2-p53 cell cycle pathways in ESC. By IHC, HER2/neu is overexpressed (2+ or 3+) in approximately 32.1% of ESC, and approximately 54.5% of cases scored as 2+ or 3+ by IHC display c-erbB2 gene amplification as assessed by fluorescent in situ hybridization. Genetic instability, typically manifested as loss of heterozygosity in multiple chromosomes, is a common feature of ESC, and one study found loss of heterozygosity at 1p32-33 in 63% of cases. A subset of ESC display protein expression patterns that are characteristic of high grade endometrial carcinomas, including loss of the metastasis suppressor CD82 (KAI-1) and epithelial-to-mesenchymal transformation, the latter manifested as E-cadherin downregulation, P-cadherin upregulation, and expression of epithelial-to-mesenchymal transformation-related molecules such as zinc-finger E-box-binding homeobox 1 (ZEB1) and focal adhesion kinase. Preliminary data suggests differential patterns of expression in ESC of some isoforms of claudins, proteases, the tumor invasiveness and progression-associated oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3), as well as a variety of other molecules. At the morphologic level, evidence that indicates that endometrial glandular dysplasia (EmGD) is the most likely morphologically recognizable precursor lesion to ESC is presented. We advocate use of the term endometrial intraepithelial carcinoma (EIC, or its other appellations) only as a morphologic descriptor and never as a diagnostic/pathologic statement of biologic potential. Given its potential for extrauterine extension, we consider the lesions described as EIC, when present in isolation, as examples of localized ESC, and patients should be managed as such. Morphologically normal, p53 immunoreactive endometrial cells (the so-called "p53 signatures"), show a statistically significant association with ESC, display p53 mutations in a significant subset, and form the start of a progression model, outlined herein, from p53 signatures to EmGD to localized ESC to the more conventionally invasive neoplasm. The identification of a morphologically-recognizable precursor holds the promise of early detection of ESC, with the attendant reduction in its overall associated mortality rate. Deciphering the molecular basis for endometrial serous carcinogenesis should uncover potential targets for diagnosis, therapy, and/or disease surveillance.
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PMID:Insights into endometrial serous carcinogenesis and progression. 1929 1


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