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)

Skin is a major target of carcinogenic trivalent arsenic (arsenite, As3+). It has been thought that cell proliferation is one of the central events involved in the carcinogenic effect of arsenite. Cyclin D1, a nuclear protein playing a pivotal role in cell proliferation and cell cycle transition from G1 to S phases, has been reported to be induced in human fibroblast by arsenite via uncertain molecular mechanisms. In the present study, the potential roles of PI-3K/Akt/IKKbeta/NFkappaB signal pathway in cyclin D1 induction by arsenite were addressed in mouse epidermal Cl41 cells. We found that exposure of Cl41 cells to arsenite was able to induce cell proliferation, activate PI-3K-->Akt/p70(S6k) signal pathway and increase cyclin D1 expression at both transcription and protein levels. Pre-treatment of Cl41 cells with PI-3K inhibitor, wortmannin, significantly inhibited the phosphorylation of Akt and p70(S6k) and thereby dramatically impaired the cyclin D1 induction by arsenite, implicating the importance of the PI-3K signal pathway in the cyclin D1 induction by arsenite. Furthermore, inhibition of PI-3K/Akt by overexpression of Deltap85 or DN-Akt blocked arsenite-induced IKK phosphorylation, IkappaBalpha degradation and cyclin D1 expression, indicating that IKK/NFkappaB is the downstream transducer of arsenite-triggered PI-3K/Akt cascade. Moreover, inhibition of IKKbeta/NFkappaB signal pathway by overexpression of its dominant negative mutant, IKKbeta-KM, also significantly blocked arsenite-induced cyclin D1 expression. Overall, arsenite exposure triggered PI-3K/Akt/IKKbeta/NFkappaB signal cascade which in turn plays essential roles in inducing cyclin D1 expression.
Carcinogenesis 2006 Apr
PMID:Essential roles of PI-3K/Akt/IKKbeta/NFkappaB pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells. 1638 40

Clinical chemoprevention trials of lung cancer have been somewhat disappointing and the development of highly effective chemopreventive agents is urgently needed. We previously showed that the organoselenium 1,4-phenylenebis(methylene)selenocyanate (p-XSC) is a potent chemopreventive agent in numerous preclinical animal models including a lung tumor model that employs carcinogens found in tobacco smoke. The goal of this study is to define molecular targets that will be highly promising in the design of future chemoprevention trials of non-small cell lung cancer (NSCLC), which is by far the most common type of lung cancer cases. In the present investigation, we showed that p-XSC at several doses (2.5, 5, 10 and 20 microM) including physiological levels (2.5-5.0 microM) of selenium is capable of inhibiting cell growth in a dose-dependent manner and inducing apoptosis in three NSCLC cells (NCI-H460, NCI-1299 and A549). To clarify the mechanism involved at the molecular level, we focused only on NCI-460 cells and examined the effects of p-XSC on markers that are known to be critical in the development of NSCLC. Using western blot analysis, we showed that p-XSC reduced the expression of cyclooxygenase-2 (COX-2) and phospholipase A2 (PLA2); although p-XSC inhibited both Akt and p-Akt but its effect was not significant. Using cDNA microarray approach (3800 genes per array) we found that p-XSC upregulates 22 genes by > or = 2-fold while downregulates 13 genes by < or = 0.5-fold; these altered genes include transcriptional factors, growth factors and those involved in xenobiotic metabolism as well as pro- and anti-apoptotic genes. Expression of selected genes was confirmed by RT-PCR; p-XSC reduced the levels of COX-2, PLA2, NF-kappaB and Cyclin D1 but enhanced the levels of glutathione peroxidase-5. Collectively, the results of this study showed that p-XSC alters several molecular markers in a manner that can account for its inhibitory effect of cell growth and induction of apoptosis; therefore, p-XSC may be considered a promising candidate for clinical chemoprevention of NSCLC.
Carcinogenesis 2006 Jul
PMID:Molecular targets of the chemopreventive agent 1,4-phenylenebis (methylene)-selenocyanate in human non-small cell lung cancer. 1639 72

We report an immunohistochemical investigation of the expression of activated extracellular signal-regulated kinase (ERK1/2) and cyclin D1 protein in both oral tongue squamous cell carcinomas (OTSCCs) and normal tongue epithelium. The expression of Ki-67 labeling index (LI) was also examined in order to evaluate cell proliferation activity. The expression of activated ERK1/2, cyclin D1 protein and Ki-67 LI were significantly stronger in OTSCCs than in normal oral mucosa (P<0.05). Both over-expression of activated ERK1/2 and positive expression of Ki-67 in OTSCCs were significantly associated with a moderately or poorly differentiated grade of carcinoma (P<0.05). Cyclin D1 immunostaining showed statistically significant association with both lymph node metastasis (P<0.05) and a tumor thickness >5mm (P<0.05). Over-expression of activated ERK1/2 was positively correlated with cyclin D1 protein expression (P<0.05, r=0.624) and cell proliferation-related indexes Ki-67 (P<0.05, r=0.723). Our results suggest that over-expression of activated ERK1/2 and cyclin D1 protein are involved in oral tongue carcinogenesis, and that activation of ERK1/2 might be related to cell cycle regulation and cell proliferation in OTSCCs.
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PMID:Activation of ERK1/2 and cyclin D1 expression in oral tongue squamous cell carcinomas: relationship between clinicopathological appearances and cell proliferation. 1648 32

Although tobacco usage and alcohol consumption are the major risk factors for oral cancer, there are individual variations in genetic susceptibility to oral cancer. The Ras pathway plays an important role in oral carcinogenesis. High percentage of Ras mutation in oral carcinoma was reported from India. Cyclin D1, a downstream member of the Ras pathway, was also shown to be overexpressed in the majority of oral cancers and the overexpression was shown to be associated with poor prognosis. In the present study, we have evaluated the association of the single nucleotide polymorphisms in the H-Ras (C81T) and cyclin D1 (A870G and C1722G) genes and oral cancer risk in 176 oral cancer cases and 142 hospital based controls matched by age and sex. All the polymorphisms studied conformed to Hardy-Weinberg equilibrium. The comparison of the CCND1 A870G and C1722G genotype frequencies in cases and controls did not show any significant association with oral cancer risk. In H-Ras C81T polymorphism, TC+CC genotype showed a one and half fold increased risk (OR=1.59) for oral cancer. On stratified analysis, the observed increased risk was more evident among men (OR=2), while such an increased risk was not seen among women. Thus, our data suggests that the variant 'C' allele of the H-Ras (C81T) is associated with a higher risk for oral carcinoma, particularly in male population and thus, this polymorphism could be a low penetrance gene predisposition factor for oral carcinoma.
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PMID:Influence of single nucleotide polymorphisms in H-Ras and cyclin D1 genes on oral cancer susceptibility. 1648 57

Cyclin D1 is one of the frequently overexpressed proteins and one of the commonly amplified genes in breast cancer. This article reviews the roles of cyclin D1 in cell-cycle regulation (normal and abnormal), mammary gland development and carcinogenesis and the relationship to oestrogen in breast tissues. It concludes by presenting the clinical, prognostic and therapeutic implications of our current knowledge of cyclin D1 in breast cancer.
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PMID:Cyclin D1 and breast cancer. 1667 18

Cyclin D1 (CCND1) regulates cellular decision between proliferation and growth arrest. Despite the functional relevance of the CCND1 A870G single nucleotide polymorphism (SNP) published results on its association with colorectal cancer (CRC) were inconsistent. We examined the association between this CCND1 genotype and CRC in the Singapore Chinese Health Study, a prospective investigation of diet and cancer in 63,000 Chinese men and women. We explored the hypothesis that inconsistency regarding the CCND1/CRC association may be attributable to the modifying effect of additional CRC risk factors. Since GSTM1/GSTT1 genotype and dietary isothiocyanate (ITC) intake had previously been identified as CRC risk factors in this cohort, we now explored if they influenced the CCND1/CRC association. In a nested case-control study within the Singapore Cohort, genomic DNA collected from 300 incident CRC cases and 1169 controls was examined for CCND1, GSTM1, GSTT1 and GSTP1 polymorphisms. Unconditional logistic regression was used to assess genotype effects on cancer risk. No main effect of CCND1 was observed, yet the CCND1 effect was influenced by ITC intake and GST genotypes. The presence of at least one CCND1 A-allele was associated with increased risk among low dietary ITC consumers (intake below median value for the cohort) with a high-activity GST profile (>or=2 of the 3 GST genotypes classified non-null or high-activity) [odds ratio (OR)=2.05; 95% confidence interval (CI), 1.10-3.82]. In contrast, the presence of at least one A-allele was associated with a decreased risk among all remaining subjects (OR=0.56; 0.36-0.86) (P for interaction=0.01). Recent studies indicate that ITCs inhibit cell proliferation and cause apoptosis through pro-oxidant properties. The results of our current study on CRC and those of our previous breast cancer study are compatible with the notion of oxidative stress in target cells as important determinant of direction and magnitude of the CCND1 effect.
Carcinogenesis 2006 Dec
PMID:The effect of the cyclin D1 (CCND1) A870G polymorphism on colorectal cancer risk is modified by glutathione-S-transferase polymorphisms and isothiocyanate intake in the Singapore Chinese Health Study. 1682 89

We have adapted the avian leukosis virus RCAS (replication-competent avian sarcoma-leukosis virus LTR splice acceptor)-mediated somatic gene transfer technique to introduce oncogenes into mammary cells in mice transgenic for the avian subgroup A receptor gene, tva, under control of the mouse mammary tumor virus (MMTV) promoter. Intraductal instillation of an RCAS vector carrying the polyoma middle T antigen (PyMT) gene (RCAS-PyMT) induced multiple, oligoclonal tumors within 3 weeks in infected mammary glands of MMTV-tva transgenic mice. The rapid appearance of these tumors from a relatively small pool of infected cells (estimated to be approximately 2 x 10(3) cells per gland by infection with RCAS carrying a GFP gene; RCAS-GFP) was accompanied by a high fraction of cells positive for Ki67, Cyclin D1, and c-Myc, implying strong proliferation competence. Furthermore, the tumors displayed greater cellular heterogeneity than did tumors arising in MMTV-PyMT mice, suggesting that RCAS-PyMT transforms a relatively immature cell type. Infection of mice transgenic for both MMTV-Wnt-1 and MMTV-tva with RCAS virus carrying an activated Neu oncogene dramatically enhanced tumor formation over what is observed in uninfected bitransgenic animals. We conclude that infection of mammary glands with retrovirus vectors is an efficient means to screen candidate oncogenes for their capacity to initiate or promote mammary carcinogenesis in the mouse.
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PMID:Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. 1709 Jun 66

As proposed by Hanahan and Weinberg (2000. Cell 100, 57-70) carcinogenesis requires crucial events such as (i) genomic instability, (ii) cell cycle deregulation, (iii) induction of a telomere length maintenance mechanism, and (iv) an angiogenic switch. By comparing the expression of p53, cyclin D1, p16, hTERT, and TSP-1 in spontaneously regressing keratoacanthoma (KA) as a paradigm of early neoplasia, with malignant invasive cutaneous squamous cell carcinoma (SCC) as a paradigm of advanced tumour development, we are now able to assign the changes in the expression of these proteins to specific stages and allocate them to defined roles in the multi-step process of skin carcinogenesis. We show that mutational inactivation of the p53 gene, and with that the onset of genomic instability is the earliest event. Individual p53-positive cells are already seen in "normal" skin, and 3/5 actinic keratoses (AKs), 5/22 KAs, and 13/23 SCCs contain p53-positive patches. Cell cycle deregulation was indicated by the overexpression of the cell cycle regulator cyclin D1, as well as by the loss of the cell cycle inhibitor p16. Interestingly, overexpression of cyclin D1 - observed in 80% of KAs and SCCs, respectively - showed a cell cycle-independent function in HaCaT cell transplants on nude mice. Cyclin D1 overexpression was associated with a massive inflammatory response, finally leading to tissue destruction. Loss of the cell cycle inhibitor p16, on the other hand, correlated with SCCs. Thus, it is tempting to suggest that overexpression of cyclin D1 is an early change that in addition to growth stimulation leads to an altered epithelial-mesenchymal interaction, while functional p16 is able to control this deregulated growth and needs to be eliminated for malignant progression. Another requirement for uncontrolled growth is the inhibition of telomere erosion by up-regulating telomerase activity. As measured by hTERT protein expression, all of the KAs and SCCs studied were positive, with a similar distribution of the protein in both groups and an expression pattern resembling that of normal epidermis. Thus, telomerase may not need to be increased significantly in skin carcinomas. Finally, we show that the angiogenesis inhibitor TSP-1 is strongly expressed in most KAs, and mainly by the tumour cells, while in SCCs the generally weak expression is restricted to the tumour-stroma. Furthermore, we provide evidence that the loss of a copy of chromosome 15 is responsible for reduced TSP-1 expression and thereby this aberration contributes to tumour vascularisation (i.e. the angiogenic switch) required for malignant growth.
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PMID:The multi-step process of human skin carcinogenesis: a role for p53, cyclin D1, hTERT, p16, and TSP-1. 1719 40

Cyclin D1 regulates G1 cell-cycle progression and is aberrantly expressed in carcinogenesis. Proteasomal degradation of cyclin D1 was highlighted as a cancer chemopreventive mechanism. To understand this mechanism better, residues responsible for degradation and ubiquitination of cyclin D1 were investigated. Eighteen lysines in cyclin D1 had single, double or multiple mutations engineered before transfection into BEAS-2B human bronchial epithelial (HBE) cells to evaluate stabilities after all-trans-retinoic acid (RA) or cycloheximide treatments. Specific mutations stabilized cyclin D1, including substitutions of lysines surrounding the cyclin box domain that inhibited RA-mediated degradation and extended the cyclin D1 half-life. Mutation of all cyclin D1 lysines blocked polyubiquitination. N-terminus (but not C-terminus) modification stabilized cyclin D1. Ubiquitination-resistant mutants preferentially localized cyclin D1 to the nucleus, directly implicating subcellular localization in regulating cyclin D1 degradation. Taken together, these findings uncover specific residues conferring ubiquitination of cyclin D1. These provide a mechanistic basis for proteasomal degradation of cyclin D1.
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PMID:Uncovering residues that regulate cyclin D1 proteasomal degradation. 1731 Sep 91

Environmental and genetic factors are important both in affecting life span and neoplastic transformation. We have shown previously that mice, which are homozygous for full-length breast cancer-associated gene-1 (Brca1) deletion and heterozygous for a p53-null mutation (Brca1(Delta11/Delta11)p53(+/-)), display premature aging and high frequency of spontaneous lymphoma and mammary tumor formation. To investigate the role of Brca1 in regulation of organ homeostasis and susceptibility of Brca1 deficiency to environmental carcinogens, we examined biological function of Brca1 in maintaining organ homeostasis and carcinogen-induced tumorigenesis. Brca1(Delta11/Delta11)p53(+/-) mice showed altered gastrointestinal tract homeostasis, including hyperkeratosis in the esophagus and forestomach. At 6 months of age, most mutant mice displayed hyperplasia in their forestomach and esophagus, leading to dysplasia and carcinoma formation in older animals. Brca1 mutant mice exhibited increased expression of Redd1, elevated reactive oxygen species and are more sensitive to oxidative stress induced lethality. Upon methyl-N-amylnitrosamine (MNAN) treatment, 70% Brca1 mutant mice developed tumors within 4 months whereas only 14% control animals developed tumor at the same period of the time. Our further analysis revealed that the tumorigenesis is accompanied by the loss of p53 and increased expression of a number of oncogenes, including Cyclin D1, phosphorylated form of Akt, beta-catenin, Runx-2 and c-Myc. These results suggest that Brca1 is involved in renewable organ homeostasis, linking the environmental and genetic factors in carcinogenesis and aging, and providing new insights into genomic instability in organism maintenance and tumorigenesis.
Carcinogenesis 2007 Jul
PMID:Absence of full-length Brca1 sensitizes mice to oxidative stress and carcinogen-induced tumorigenesis in the esophagus and forestomach. 1736 41


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