Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The F-box protein Skp2 positively regulates the G1-S transition by promoting degradation of the cyclin-dependent kinase inhibitor p27(kip1) (p27). Recent evidence has suggested an oncogenic role of Skp2 in not only carcinogenesis but also lymphomagenesis. In this study, we performed immunohistochemical analysis on the cell-cycle-associated proteins, Skp2, p27, and Ki-67, in 27 patients with de novo diffuse large B-cell lymphoma (DLBCL), evaluating the correlation between the clinical characteristics and expression levels of these proteins. The patients were classified into two groups according to the positivity for Skp2 expression: a high Skp2 expression group (>60% positive for Skp2 in lymphoma cells) and a low Skp2 expression group (< or = 60%). A high level of Skp2 expression significantly correlated with advanced clinical stage (P = 0.029), although the increase did not correlate with age, gender, LDH levels, presence of extranodal disease, or performance status and resulted in no correlation with the International Prognostic Index-based risk grading. However, it was noteworthy that the high Skp2 expression group demonstrated a significantly worse prognosis than the low Skp2 expression group (P = 0.0007). The expression level of Skp2 correlated with that of Ki-67 but not necessarily with that of p27. The p27 expression level did not correlate patients' prognosis. Taken together, it was suggested that Skp2 was a valuable and independent marker predicting the outcome in DLBCL.
 ...
PMID:Prognostic significance of the F-box protein Skp2 expression in diffuse large B-cell lymphoma. 1287 24

Helicobacter pylori infection is associated with increased gastric epithelial cell turnover and is a risk factor for noncardia gastric cancer. H. pylori reduces the expression of p27 protein, a cyclin-dependent kinase inhibitor of the G(1) to S-phase cell cycle transition and gastric tumor suppressor gene. Although cell cycle dysregulation associated with decreased p27 may contribute to gastric carcinogenesis, how H. pylori reduces p27 in gastric epithelial cells remains unknown. In the present study, we investigated the mechanisms of the p27 decrease, using AGS and MKN28 gastric epithelial cells cocultured with H. pylori strains under conditions of defined cell cycle distribution. The expression of p27 protein was reduced by H. pylori in a dose- and time-dependent manner. Northern blot and pulse-chase analyses revealed that this reduction was not regulated at a transcriptional level but by accelerated p27 degradation via a proteasome-dependent pathway. Despite up-regulation of the proteasome-dependent degradation of p27 protein, neither threonine 187-phosphorylated p27 nor skp2 (the ubiquitin ligase for p27) were increased. Furthermore, H. pylori impaired p27 ubiquitination and did not increase global proteasomal function. These results indicate that H. pylori increases the degradation of p27 through a proteasomal pathway distinct from the physiological pathway that degrades p27 during cell cycle progression. Putative virulence genes of H. pylori (cagA, cagE, or vacA) played no role in reducing p27 expression. Increased degradation of p27 by H. pylori through a proteasome-dependent, ubiquitin-independent pathway may contribute to the increased risk of gastric cancer associated with chronic H. pylori infection.
 ...
PMID:Helicobacter pylori increases proteasome-mediated degradation of p27(kip1) in gastric epithelial cells. 1290 57

Ultraviolet (UV) irradiation has been involved in both initiation and promotion of carcinogenesis in melanoma. Alterations of cellular proliferation proteins, such as p73, Nup88, Id1 and p27 have been considered to play critical roles in melanoma development. However, the molecular mechanisms behind melanoma carcinogenesis are still poorly understood. In this study, we used human skin melanocytes as an experimental model system to investigate effects of UV irradiation on protein expression concerning cellular proliferation. The melanocytes prepared from human foreskin were separately exposed to various doses of UVA or UVB and post-cultivated for 24 or 48 h. Total proteins were isolated from the melanocytes, and expression of p73, Nup88, Id1, p27, bcl-2 and proliferating cell nuclear antigen (PCNA) proteins was examined by western blotting and immunocytochemistry. Results showed that expression of p73 and Nup88 was enhanced by UVA irradiation in a dose- and time-dependent manner. However, expression of Id1, p27, bcl-2 and PCNA proteins was not changed upon exposure to the UVA. Id1 and p27 proteins were over-expressed by exposure to UVB, but expression of p73, Nup88, bcl-2 and PCNA proteins was not changed by the UVB irradiation. The data suggested that UVA and UVB irradiation might lead to alterations of the different intracellular proteins. UVA enhanced protein expression concerning cell growth (p73 and Nup88) and UVB might over-express proteins concerning cellular proliferation (Id1 and p27). UVA and UVB may induce initiation of melanoma via separate intracellular pathways.
Carcinogenesis 2003 Dec
PMID:Ultraviolet A and B differently induce intracellular protein expression in human skin melanocytes--a speculation of separate pathways in initiation of melanoma. 1451 52

Prostate cancer is among the most common malignancies. It is estimated that 1 in 6 men in the United States will be diagnosed with this disease. Despite the high prevalence and importance of prostate cancer, the molecular mechanisms underlying its development and progression remain poorly understood. This article reviews new information about the roles of oxidants and electrophiles in prostate cancer; the potential importance of chronic inflammation and atrophy in prostate carcinogenesis, and implications for chemoprevention; evidence supporting telomere shortening and genetic instability in the etiology of prostate cancer; and alpha-methylacyl-coenzyme A racemase (AMACR) as a potential marker for prostate carcinogenesis. These new results show that at least some high-grade prostatic intraepithelial neoplasias (PIN) and early adenocarcinomas appear to arise from proliferative inflammatory atrophy (PIA). Inflammation and other environmental factors may lead to the destruction of prostate epithelial cells, and increased proliferation may occur as a response to this cell death. Such proliferation may be mechanistically related to decreased p27(Kip1) observed in PIA. The decreased apoptosis associated with these events may also be related to increased expression of Bcl-2. Increased oxidant and electrophile stress in the setting of increased proliferation associated with these events may lead to elevated glutathione S-transferase P1 (GSTP1) expression as a genomic-protective measure. However, aberrant methylation of the CpG island of the GSTP1 gene promoter silences GSTP1 gene expression and protein levels, setting the stage for additional genetic damage and accelerated progression toward PIN and carcinoma. Additional results show that AMACR may be an important new marker of prostate cancer, and its use in combination with p63 staining may provide the basis for an improved method for identification of prostate cancer.
 ...
PMID:Human prostate cancer precursors and pathobiology. 1460 18

The cyclin-dependent kinase inhibitor, p27, has been shown to mediate cell growth arrest thereby significantly reducing the percentage of proliferating cells. It seems that p27 expression is essential for the control of normal endometrial proliferation, and reduced or absent p27 expression may be an important step in endometrial carcinogenesis. Our aim was to demonstrate the effects of tamoxifen therapy on the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. Fifty-three pre- and post-tamoxifen treatment endometrium samples were examined immunohistochemically using p27 antibody. Tamoxifen therapy (20 mg/day) for 60 days increased the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. We conclude that tamoxifen therapy does not seem to be directly involved in the carcinogenesis of endometrial carcinoma since the expression of p27 is not decreased.
 ...
PMID:Effects of tamoxifen therapy on the expression of p27 protein in the endometrium of women with primary breast cancer. 1461 25

The proliferating zone contains stem cells that give rise to all epithelial cells of the gastric mucosa. In the present study, we investigated the turnover of gastric epithelial cells in the proliferating zone of Helicobacter pylori-infected mucosa, with or without intestinal metaplasia, before and after eradication of the microorganism. In addition, we studied the topographical distribution of the cyclin dependent kinase inhibitor p27(Kip1), which plays a critical role in cell cycle progression and differentiation programs. Twenty-eight patients (22 male), aged 32-78 years and with dyspeptic symptoms, were endoscoped, and gastric biopsies were obtained from antrum and corpus for histopathological examination and the Campylobacter-like organisms test; eradication therapy was given to infected patients, and all patients were re-endoscoped after 105 +/- 33 days (mean +/- SD). The kinetics of gastric epithelial cells and p27(Kip1) status was assessed by means of immunohistochemistry and TUNEL (Tdt-mediated dUTP-biotin nick end labeling) assay. Twenty-one (21) of 28 patients were H. pylori positive, and 7 were found H. pylori negative and served as controls. In antrum, intestinal metaplasia was detected in 7/21 (33.3%). In H. pylori gastritis, Ki67 expression was found increased in the proliferating zone, compared with normal (P =.03); analogous results were obtained with the other proliferation markers, namely retinoblastoma protein and topoisomerase IIalpha. An inverse relationship between proliferation index and atrophy was disclosed (P =.02). A reduction in the proliferation index was observed after eradication, albeit not significant. Apoptotic epithelial cells were found significantly increased (P <.01) in H. pylori gastritis, and a significant reduction was observed after eradication (P <.01). In addition, apoptotic index was found to correlate with H. pylori density. The topographical study of p27(Kip1) revealed a p27(kip1)-positive epithelial cell population that resided deep in the proliferating zone; these cells were considered to be stem cells and were found significantly increased in areas with intestinal metaplasia (P <.05); in H. pylori gastritis, there was also an increase that did not reach statistical significance. H. pylori infection induces apoptosis and increases proliferation in the proliferating zone. The increased cellular turnover, together with the increased number of putative p27(Kip1)-positive stem cells in the context of intestinal metaplasia, provides further evidence for the role of H. pylori infection in gastric carcinogenesis.
 ...
PMID:Alterations in the proliferating compartment of gastric mucosa during Helicobacter pylori infection: the putative role of epithelial cells expressing p27(kip1). 1461 46

Silymarin, a defined mixture of natural flavonoid, has recently been shown to have potent cancer chemopreventive efficacy against colon carcinogenesis in rat model; however, the mechanism of such efficacy is not elucidated. Here, using pure active agent in silymarin, namely silibinin, we show its antiproliferative and apoptotic effects, and associated molecular alterations in human colon carcinoma HT-29 cells. Silibinin treatment of cells at 50-100 microg/ml doses resulted in a moderate to very strong growth inhibition in a dose- and a time-dependent manner, which was largely due to a G0/G1 arrest in cell cycle progression; higher dose and longer treatment time also caused a G2/M arrest. In mechanistic studies related its effect on cell cycle progression, silibinin treatment resulted in an upregulation of Kip1/p27 and Cip1/p21 protein as well as mRNA levels, and decreased CDK2, CDK4, cyclin E and cyclin D1 protein levels together with an inhibition in CDK2 and CDK4 kinase activities. In other studies, we observed that G2/M arrest by silibinin was associated with a decrease in cdc25C, cdc2/p34 and cyclin B1 protein levels, as well as cdc2/p34 kinase activity. In the studies assessing biological fate of silibinin-treated cells, silibinin-induced cell cycle arrest and growth inhibition were not associated with cellular differentiation, but caused apoptotic death. The quantitative apoptosis analysis showed up to 15% apoptotic cell death after 48 h of silibinin treatment. Interestingly, silibinin-induced apoptosis in HT-29 cells was independent of caspases activation, as all caspases inhibitor did not reverse silibinin-induced apoptosis. This observation was further confirmed by the findings showing a lack in caspases activity increase and caspases and PARP cleavage as well as a lack in cytochrome c release in cytosol following silibinin treatment of HT-29 cells. Additional studies conducted in mice showed that silibinin doses found effective in HT-29 cells are achievable in plasma, which increases the significance of the present findings and their possible translation in in vivo anticancer efficacy of silibinin against colon cancer. Together, these results identify molecular mechanisms of silibinin efficacy as a cell cycle regulator and apoptosis inducer in human colon carcinoma HT-29 cells, and justify further studies to investigate potential usefulness of this nontoxic agent in colon cancer prevention and intervention.
 ...
PMID:Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. 1461 51

Although arsenic exposure causes liver disease and/or hepatoma, little is known about molecular mechanisms of arsenic-induced liver toxicity or carcinogenesis. We investigated the effects of arsenic on expression of cancer-related genes in a rat liver following subchronic exposure to sodium arsenate (1, 10, 100 ppm in drinking water), by using real-time quantitative RT-PCR and immunohistochemical analyses. Arsenic accumulated in the rat liver dose-dependently and caused hepatic histopathological changes, such as disruption of hepatic cords, sinusoidal dilation, and fatty infiltration. A 1-month exposure to arsenic significantly increased hepatic mRNA levels of cyclin D1 (10 ppm), ILK (1 ppm), and p27(Kip1) (10 ppm), whereas it reduced mRNA levels of PTEN (1 ppm) and beta-catenin (100 ppm). In contrast, a 4-month arsenic exposure showed increased mRNA expression of cyclin D1 (100 ppm), ILK (1 ppm), and p27(Kip1) (1 and 10 ppm), and decreased expression of both PTEN and beta-catenin at all 3 doses. An immunohistochemical study revealed that each protein expression accords closely with each gene expression of mRNA level. In conclusion, subchronic exposure to inorganic arsenate caused pathological changes and altered expression of cyclin D1, p27(Kip1), ILK, PTEN, and beta-catenin in the liver. This implies that arsenic liver toxicity involves disturbances of some cancer-related molecules.
 ...
PMID:Subchronic exposure to arsenic through drinking water alters expression of cancer-related genes in rat liver. 1471 50

The steroid hormone 1,25-dihydroxyvitamin D(3), [1,25(OH)(2)D(3), calcitriol], the active metabolite of vitamin D, exerts pleiotropic antitumor effects against several malignancies. However, the clinical use of this hormone is limited by hypercalcemia. 25-Hydroxyvitamin D(3), the prohormone of 1,25(OH)(2)D(3), is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-alpha-hydroxylase [1 alpha(OH)ase]. 1 alpha(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1 alpha(OH)ase is highly expressed in both normal and malignant pancreatic tissue. Expression of this enzyme and enzymatic activity was also detected in four pancreatic tumor cell lines. 25(OH)D(3) inhibited the growth of three of four pancreatic cell lines in a manner that correlated with the level of induction of the cyclin-dependent kinase inhibitors p21 and p27 and with the induction of cell cycle arrest at the G(1)/S checkpoint. The growth of a cell line stably transfected with a mutant Ki-ras allele and of a second cell line with an endogenous Ki-ras activating mutation was also inhibited by 25(OH)D(3), indicating that activating Ki-Ras mutations, which occur in almost 90% of pancreatic adenocarcinomas, do not interfere with the growth-inhibitory effects of 25(OH)D(3). The expression of 1 alpha(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D(3) may offer possible therapeutic and chemopreventive options for pancreatic cancer.
Carcinogenesis 2004 Jun
PMID:Pancreatic cancer cells express 25-hydroxyvitamin D-1 alpha-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3. 1474 20

The increased expression of cyclooxygenase (COX)-2 significantly enhances carcinogenesis and inflammatory reactions, and its regulation may be a reasonable target for cancer chemoprevention. We demonstrated previously that deguelin inhibits proliferation of premalignant human bronchial epithelial (HBE) cells, such as 1799 cells and squamous HBE cells, by regulating phosphatidylinositol-3-kinase Akt activity, which is involved in COX-2 expression. We sought to determine the effect of deguelin on COX-2 expression in squamous HBE cells. Deguelin strongly inhibited COX-2 expression in squamous HBE cells, without affecting the COX-1 protein level. Deguelin inhibited proliferation of a variety of non-small cell lung carcinoma (NSCLC) cell lines through apoptosis and induced Bax expression in the H322 NSCLC and squamous HBE cells. Deguelin treatment did not affect Bcl-2 protein levels but increased expression levels of the proapoptotic protein p53 and the cyclin-dependent kinase inhibitors p21 and p27 in the squamous HBE cells. The sensitivity of the squamous HBE and NSCLC cells to deguelin and the inhibitory effects of deguelin on COX-2 expression in the squamous HBE cells indicate that regulation of COX-2 expression is involved in the chemopreventive action of deguelin in lung cancer.
 ...
PMID:Deguelin-induced inhibition of cyclooxygenase-2 expression in human bronchial epithelial cells. 1487 87


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>