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)

Increases in cell proliferation are widely viewed as being of importance in carcinogenesis. We report that exposure of normal human lung fibroblasts to a low dose of alpha particles like those emitted by radon/radon progeny stimulates their proliferation in vitro, and this response also occurs when unirradiated cells are treated with supernatants from alpha-irradiated cells. We attribute the promitogenic response to superoxide dismutase- and catalase-inhibitable a particle-induced increases in the concentrations of transforming growth factor beta1 (TGF-beta1) in cell supernatants. TGF-beta1 at concentrations commensurate with those in the supernatants capably induces increases in intracellular reactive oxygen species (ROS) in unirradiated cells. Furthermore, the addition of supernatants from alpha-irradiated cells to unirradiated cells decreases cellular levels of TP53 and CDKN1A and increases CDC2 and proliferating cell nuclear antigen in the latter. Like the increased intracellular ROS bystander effect, this "decreased TP53/CDKN1A response" can be mimicked in otherwise untreated cells by the addition of low concentrations of TGF-beta1. Our results indicate that alpha particle-associated increases in cell growth correlate with intracellular increases in ROS along with decreases in TP53 and CDKN1A, and that these cellular responses are mechanistically coupled. As well, the proliferating cell nuclear antigen and CDC2 increases that occur along with the decreased TP53/CDKN1A bystander effect also would expectedly favor enhanced cell growth. Such processes may account for cell hyperplastic responses in the conducting airways of the lower respiratory track that occur after inhalation exposure to radon/ radon progeny, as well as, perhaps, other ROS-associated environmental stresses.
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PMID:Factors underlying the cell growth-related bystander responses to alpha particles. 1072 89

Carcinogenesis is a multistage process with sequences of genetic events that govern the phenotypic expression of a series of transformation steps that lead to the development of metastatic cancer. To better understand the mechanisms involved in human bronchial carcinogenesis induced by alpha particles from radon, we have developed a model of neoplastic transformation based on human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells. Cells exposed to alpha particles become tumorigenic after progressing through a series of sequential stages including altered growth pattern, resistance to serum-induced terminal differentiation, agar-positive growth, tumorigenicity, and metastasis, with each step representing a necessary yet insufficient step toward the later, more malignant phase. Cell fusion studies indicated that the radiation-induced tumorigenic phenotype in BEP2D cells can be completely suppressed by fusion with nontumorigenic BEP2D cells. Several cellular differentiation and growth regulation genes such as DCC (deleted in colorectal cancer), CDKN1A (also known as p21(C1P1)) and the gene that encodes DNA-PK were frequently found to be modulated in tumorigenic BEP2D cells and may be related to the process of carcinogenesis.
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PMID:Mechanisms of radiation-induced neoplastic transformation of human bronchial epithelial cells. 1112 Dec 39

The cdknlA gene encodes CDKN1A, a protein that regulates cell cycle progression, terminal differentiation, and apoptosis. Polymorphisms or loss of heterozygosity of this usually biallelically expressed gene have no major impact on carcinogenesis. The prevalence of somatic mutations in malignancies is low. Gene rearrangements involving cdknlA are scarce. CDKN1A is expressed in both premalignant and malignant lesions. While the prognostic value of nuclear CDKN1A expression is controversial, the prognostic value of its recently discovered cytoplasmic accumulation is simply unknown. CDKN1A translocates from the nucleus to the cytoplasm when cleaved by caspase-like activities during early apoptosis. The presence of cytoplasmic catabolites (e.g.: p14) might therefore indicate apoptosis. We found no correlation between nuclear and cytoplasmic anti-CDKN1A immunoreactivity in our samples of oropharyngeal squamous cell carcinoma. CDKN1A Cap20, CDKN1, CDKN1A, CDKNA1, Cip-1, Mda-6, P21, Pic1, Sdi-1, Waf-1.
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PMID:Cyclin-dependent kinase-inhibitor 1 (CDKN1A) in the squamous epithelium of the oropharynx: possible implications of molecular biology and compartmentation. 1129 59

Pancreatic cancer (PC) is thought to develop through a series of duct lesions termed pancreatic intraepithelial neoplasia (PanIN). Characterization of the molecular pathology of these lesions may lead to additional understanding of pancreatic ductal carcinogenesis. We examined the protein expression of four functionally related genes, p21(WAF1/CIP1) (CDKN1A), p53, cyclin D1 (CCND1), and DPC4/Smad4 (MADH4), aberrations of which are associated with PC, within 451 PanIN lesions present in the pancreata of 60 patients. p21(WAF1/CIP1) overexpression was present in the normal ducts of 9% of patients and increased progressively to 16% of patients with PanIN-1A lesions, to 32% of patients with PanIN-1B lesions, 56% of patients with PanIN-2 lesions, 80% of patients with PanIN-3 lesions, and 85% of patients with invasive carcinomas (P < 0.01). p53 and cyclin D1 overexpression occurred predominantly in PanIN-3 lesions (P < 0.01), and loss of DPC4/Smad4 expression occurred predominantly in PanIN-3 lesions and invasive carcinoma (P < 0.01). In addition, p21(WAF1/CIP1) overexpression occurred independently of p53 and DPC4/Smad4 expression within invasive carcinoma and PanIN-3 lesions. Cyclin D1 overexpression or loss of DPC4/Smad4 expression was apparent in 85% of invasive carcinomas but in only 14% of PanIN-2 lesions. These data demonstrate that overexpression of p21(WAF1/CIP1) occurs early in the development of PanIN, before aberrations in p53, cyclin D1, and DPC4/Smad4 expression. p21(WAF1/CIP1) overexpression, independent of p53 and/or DPC4/Smad4 expression, may reflect increased Ras activity, either directly through activating K-ras mutations or as a consequence of HER-2/neu (ERBB2) overexpression, both of which are common in PC and in early events in the development of PanIN. These data support further the current progression model for PC and demonstrate that aberrant expression of key cell cycle regulatory genes may be important in the early development and progression of PanIN.
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PMID:Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. 1175 5

In the past, most mechanistic studies of ionizing radiation response have employed very large doses, then extrapolated the results down to doses relevant to human exposure. It is becoming increasingly apparent, however, that this does not give an accurate or complete picture of the effects of most environmental exposures, which tend to be of low dose and protracted over time. We have initiated direct studies of low dose exposures, and using the relatively responsive ML-1 cell line, have shown that changes in gene expression can be triggered by doses of gamma-rays of 10 cGy and less in human cells. We have now extended these studies to investigate the effects on gene induction of reducing the rate of irradiation. In the ML-1 human myeloid leukemia cell line, we have found that reducing the dose rate over three orders of magnitude results in some protection against the induction of apoptosis, but still causes linear induction of the p53-regulated genes CDKN1A, GADD45A, and MDM2 between 2 and 50 cGy. Reducing the rate of exposure reduces the magnitude of induction of CDKN1A and GADD45A, but not the magnitude or duration of cell cycle delay. In contrast, MDM2 is induced to the same extent regardless of the rate of dose delivery. Microarray analysis has identified additional low dose-rate-inducible genes, and indicates the existence of two general classes of low dose-rate responders in ML-1. One group of genes is induced in a dose rate-dependent fashion, similar to GADD45A and CDKN1A. Functional annotation of this gene cluster indicates a preponderance of genes with known roles in apoptosis regulation. Similarly, a group of genes with dose rate-independent induction, such as seen for MDM2, was also identified. The majority of genes in this group are involved in cell cycle regulation. This apparent differential regulation of stress signaling pathways and outcomes in response to protracted radiation exposure has implications for carcinogenesis and risk assessment, and could not have been predicted from classical high dose studies.
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PMID:Differential responses of stress genes to low dose-rate gamma irradiation. 1269 64

Environmental contaminants possessing hormonal activity have long been suspected of playing a role in cancer causation. What is unclear is whether such agents elicit their effects through genotoxic and/or epigenetic mechanisms. gamma-Hexachlorocyclohexane (gamma-HCH, lindane) was tested in the 10(-12)-10(-4) M range. Chromosomal damage in MCF-7 breast cells and PC-3 prostate cells was assessed using the cytokinesis block micronucleus assay. Micronuclei (MNi) were scored in 1000 binucleate cells per treatment. Cell viability and cell cycle kinetics were also assessed, along with immunocytochemical and quantitative gene expression analyses of CDKN1A (P21WAF1/CIP1), BCL-2 and BAX. Following 24 h treatment, lindane (10(-12)-10(-10) M) induced increases (up to 5-fold) in MNi in both cell lines. Increases in MNi occurred in the absence of DNA single-strand breaks or cytotoxicity and, compared with benzo[a]pyrene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, at low concentrations. Lindane induced more MNi than the alpha or beta stereoisomers of HCH. Low dose lindane (10(-12)-10(-10) M) significantly elevated the percentage of MCF-7 cells staining positive for Bcl-2 and of PC-3 cells staining positive for Bax. Only high dose lindane (10(-4) M) disrupted cell cycle kinetics with increases in percentage of cells in G1 and decreases in percentage of cells in G2/M. Despite a comparable high dose lindane induction of cell cycle arrest, marked increases in expression of P21WAF1/CIP1 were observed only in MCF-7 cells, although in PC-3 cells a significant increase (P < 0.0005) in the percentage of cells staining positive for p21Waf1/Cip1 was seen. These results suggest that 'environmental' concentrations of lindane can induce a number of subtle alterations in breast and prostate cells in the absence of cytotoxicity.
Carcinogenesis 2004 Apr
PMID:Low dose induction of micronuclei by lindane. 1468 26

There is little primate risk factor data in the literature evaluating the relationship between proposed mechanisms of PPAR agonist-induced hepatocarcinogenesis at clinically relevant therapeutic exposures. These studies were conducted to characterize the hepatic effects of fenofibrate and ciprofibrate in the cynomolgus monkey. Male cynomolgus monkeys were given fenofibrate (250, 1250 or 2500 mg/kg/day) or ciprofibrate (3, 30, 150 or 400 mg/kg/day) for up to 15 days. The highest doses used were approximately 4 times (fenofibrate) and 9.4 times (ciprofibrate) the human therapeutic exposure for these agents based on AUC (area under the curve). For both compounds, there was a treatment-related increase in liver weight and periportal hepatocellular hypertrophy, which was related to increases in peroxisomes (up to 2.8 times controls) and mitochondria (up to 2.5 times controls). An increase in smooth endoplasmic reticulum probably contributed to the hypertrophy. There was no indication of cell proliferation as determined by the number of mitotic figures and this was confirmed by evaluating cell proliferation by immunohistochemical staining for the Ki-67 antigen. Consistent with the findings by light microscopy, there was no treatment-related effect on the level of mRNA for proteins known to be involved in the control of hepatocyte cell division or apoptosis (e.g. P21, Cyclin D1, PCNA, CDKN1A). Furthermore, there was minimal indication of oxidative stress. Thus, there was no evidence of lipofuscin accumulation, and there was no remarkable increase in the mRNA levels for most proteins known to respond to oxidative stress (e.g. catalase, glutathione peroxidase). A mild induction in the mRNA levels of cellular beta-oxidation and detoxification enzymes (e.g. acyl CoA oxidase, thioredoxin reductase) was observed. Collectively, the data from these studies suggest that the primate responds to PPARalpha agonists in a manner that is different from the rodent suggesting that the primate may be refractory to PPAR-induced hepatocarcinogenesis.
Carcinogenesis 2004 Sep
PMID:Fibrates induce hepatic peroxisome and mitochondrial proliferation without overt evidence of cellular proliferation and oxidative stress in cynomolgus monkeys. 1513 Oct 11

Genetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mouse mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (>300,000 mouse mammary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (>2.5 million human breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all of the tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKBalpha), GADD45B, and CDKN1A (p21); transcription-related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets. This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.
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PMID:From mice to humans: identification of commonly deregulated genes in mammary cancer via comparative SAGE studies. 1552 Jan 79

The p21 (Waf1/Cip1/CDKN1A) protein regulates the transition from the G1 to the S phase and has an important role in modulating cell-cycle control, apoptosis and cell growth. Two polymorphisms of the p21 gene at codon 31 (p21 C98A, dbSNP rs1801270) and at the 3' untranslated region (p21 T70C, dbSNP rs1059234) may have an effect on the protein function and may thus play a role in the development of cancer. We hypothesized that these two p21 polymorphisms are associated with the risk of squamous cell carcinoma of the head and neck (SCCHN). We tested this hypothesis in a hospital-based case-control study of 712 patients newly diagnosed with SCCHN and 1222 cancer-free controls who were frequency-matched by age, sex and ethnicity. All subjects were non-Hispanic whites. Our results showed that the variant alleles and genotypes were more common among cases than among controls (P < 0.001 and P = 0.013 for p21C70T, and P < 0.001 and P = 0.035 for p21C98A, respectively). Compared with the p21 70CC genotype, there was a significantly greater risk of SCCHN associated with the variant p21 70TC [odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.12-1.93] and combined p21 70TC/TT (OR = 1.49, 95% CI = 1.14-1.95) genotypes. Similarly, compared with the p21 98CC genotype, there was also a significantly greater SCCHN risk associated with the variant p21 98AC (OR = 1.32, 95% CI = 1.00-1.73) and combined p21 98AC/AA (OR = 1.37, 95% CI = 1.05-1.79) genotypes. When these two polymorphisms were evaluated together by the number of risk alleles, there was a significant increase in SCCHN risk that was dependent on the number of risk alleles (P(trend) = 0.001). Our results suggest that the presence of these two p21 polymorphisms may be a marker of genetic susceptibility to SCCHN.
Carcinogenesis 2005 Sep
PMID:Genetic polymorphisms of p21 are associated with risk of squamous cell carcinoma of the head and neck. 1587 16

Mutations leading to the alteration of cell-cycle checkpoint functions are a common feature of most cancers. Because of the highly regulated nature of the cell cycle, it seems likely that variation in gene dosage of key components due to functional regulatory polymorphisms could play an important role in cancer development. Here we provide evidence of the involvement of promoter single-nucleotide polymorphisms (pSNPs) in the cyclin-dependent-kinase inhibitor genes CDKN2A, CDKN2B, CDKN1A, and CDKN1B in the etiology of childhood pre-B acute lymphoblastic leukemia (ALL). A case-control study, conducted in 240 patients with pre-B ALL and 277 healthy controls, combined with a family-based analysis using 135 parental trios, all of French-Canadian origin, were used to evaluate single-site genotypic as well as multilocus haplotypic associations for a total of 10 pSNPs. Using both study designs, we showed evidence of association between variants CDKN2A -222A, CDKN2B -593A, and CDKN1B -1608A, and an increased risk of ALL. These findings suggest that variable expression levels of cell-cycle inhibitor genes CDKN2A, CDKN2B, and CDKN1B due to regulatory polymorphisms could indeed influence the risk of childhood pre-B ALL and contribute to carcinogenesis.
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PMID:Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia. 1700 50


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