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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In cancer, Transforming Growth Factor beta (TGFbeta) increases proliferation and promotes invasion via selective loss of signalling pathways. Oesophageal adenocarcinoma arises from Barrett's oesophagus, progresses rapidly and is usually fatal. The contribution of perturbed TGFbeta signalling in the promotion of metastasis in this disease has not been elucidated. We therefore investigated the role of TGFbeta in Barrett's associated oesophageal adenocarcinoma using a panel of cell lines (OE33, TE7, SEG, BIC, FLO). 4/5 adenocarcinoma cell lines failed to cell cycle arrest, down-regulate c-Myc or induce p21 in response to TGFbeta, and modulation of a Smad3/4 specific promoter was inhibited. These hyperproliferative adenocarcinoma cell lines displayed a TGFbeta induced increase in the expression of the extracellular matrix degrading proteinases, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1), which correlated with an invasive cell phenotype as measured by in vitro migration, invasion and cell scattering assays. Inhibiting ERK and JNK pathways significantly reduced PAI and uPA induction and inhibited the invasive cell phenotype. These results suggest that TGFbeta Smad-dependent signalling is perturbed in Barrett's carcinogenesis, resulting in failure of growth-arrest. However, TGFbeta can promote PAI and uPA expression and invasion through MAPK pathways. These data would support a dual role for TGFbeta in oesophageal adenocarcinoma.
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PMID:Selective loss of TGFbeta Smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines. 1726 80

Cells from patients with genomic instability syndromes have high predisposition to cancer. However, little is known about whether these mutant cells have high susceptibility to oncogenic transformation. We have tested the hypothesis that a defect in maintaining genome integrity is necessary but not sufficient alone for oncogenic transformation and needs to collaborate with other signals in order to produce full oncogenic transformation. Using genetically matched primary cells deficient for the Fanconi complementation group C gene (Fancc) and the ataxia telangiectasia mutated gene (Atm), we found that certain forms of oncogenic activation and cooperation require a combination of genomic instability with increased expression of nucleophosmin (NPM) to prevent oncogenic stress-induced apoptosis or senescence. Intriguingly, co-expression of c-Myc and NPM leads to a synergistic increase in the proliferation rate in Fancc-/- or Atm-/- cells. Analysis of p53 stabilization and activation by c-Myc demonstrates that over-expression of NPM significantly reduces the accumulation of the activated p53 but not the stability of p53. Moreover, NPM is shown to enhance transforming activity of co-expressed Myc and Ras in wild-type and, to a greater degree, in Fancc-/- or Atm-/- cells, suggesting a role in oncogenic cooperation. Finally, a partial knockdown of NPM is sufficient to cause massive apoptosis in Fancc-/- or Atm-/- cells co-expressing c-Myc and Ras while sparing untransformed cells. Our study demonstrates a novel mechanism of NPM tumorigenesis by establishing NPM as a crucial inhibitor of oncogene-induced apoptosis and senescence.
Carcinogenesis 2007 Jun
PMID:Nucleophosmin suppresses oncogene-induced apoptosis and senescence and enhances oncogenic cooperation in cells with genomic instability. 1727 30

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

The proto-oncogene c-Myc is involved in early neoplastic transformations. Two consensus Lef/Tcf binding elements (TBE) were found to be prerequisite for transcriptional transactivation by the armadillo proteins beta-catenin and plakoglobin (PG) together with Tcf4 in human neoplastic cells. In epidermal keratinocytes, c-Myc was reported to be repressed by Lef-1 and PG. Using reporter gene assays, here we demonstrate that deletion of the two consensus TBE fails to abrogate transcriptional regulation by Lef-1/PG in wildtype and beta-catenin-/- keratinocytes, while it reduces transcription in pre-neoplastic PG-/- keratinocytes. We identified a TBE sequence variant downstream of the major transcriptional initiation site that binds Lef-1 in vitro and in vivo, and its mutation compromised transcriptional regulation by Lef-1/PG. Collectively, this study demonstrates that the two consensus TBE's reported in neoplastic cells are dispensable for c-Myc regulation in normal keratinocytes, which instead use a novel TBE sequence variant. This unprecedented finding may have important implications for armadillo target genes involved in carcinogenesis.
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PMID:Keratinocyte transcriptional regulation of the human c-Myc promoter occurs via a novel Lef/Tcf binding element distinct from neoplastic cells. 1746 81

Peroxisome proliferators are potent rodent liver carcinogens that act via a non-genotoxic mechanism. The mode of action of these agents in rodent liver includes increased cell proliferation, decreased apoptosis, secondary oxidative stress and other events; however, it is not well understood how peroxisome proliferators are triggering the plethora of the molecular signals leading to cancer. Epigenetic changes have been implicated in the mechanism of liver carcinogenesis by a number of environmental agents. Short-term treatment with peroxisome proliferators and other non-genotoxic carcinogens leads to global and locus-specific DNA hypomethylation in mouse liver, events that were suggested to correlate with a burst of cell proliferation. In the current study, we investigated the effects of long-term exposure to a model peroxisome proliferator WY-14,643 on DNA and histone methylation. Male SV129mice were fed a control or WY-14,643-containing (1000ppm) diet for one week, five weeks or five months. Treatment with WY-14,643 led to progressive global hypomethylation of liver DNA as determined by an HpaII-based cytosine extension assay with the maximum effect reaching over 200% at five months. Likewise, trimethylation of histone H4 lysine 20 and H3 lysine 9 was significantly decreased at all time points. The majority of cytosine methylation in mammals resides in repetitive DNA sequences. In view of this, we measured the effect of WY-14,643 on the methylation status of major and minor satellites, as well as in IAP, LINE1 and LINE2 elements in liver DNA. Exposure to WY-14,643 resulted in a gradual loss of cytosine methylation in major and minor satellites, IAP, LINE1 and LINE2 elements. The epigenetic changes correlated with the temporal effects of WY-14,643 on cell proliferation rates in liver, but no sustained effect on c-Myc promoter methylation was observed. Finally, WY-14,643 had no effect on DNA and histone methylation status in Pparalpha-null mice at any of the time points considered in this study. These data indicate the importance of epigenetic alterations in the mechanism of action of peroxisome proliferators and the key role of Pparalpha.
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PMID:Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor alpha. 1758 32

Deregulation of beta-catenin signaling is an important event in the genesis of several human malignancies including prostate cancer. We investigated the effects of apigenin, a naturally occurring plant flavone, on prostate carcinogenesis in TRAMP mice and further elucidated its mechanism of action. Oral intake of apigenin by gavage at doses of 20 and 50 microg/mouse/d, 6 days per week for 20 weeks, significantly decreased tumor volumes of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver in TRAMP mice. Apigenin-treated mice had significantly diminished weights of their genitourinary apparatuses and dorsolateral and ventral prostate lobes, compared with the control group, and showed reduced proliferation and increased apoptosis in the dorsolateral prostates, which correlated with elevated plasma apigenin levels. Continuous intake of apigenin up to 50 weeks by TRAMP mice significantly improved their overall survival. P.o. administration of apigenin further resulted in increased levels of E-cadherin and decreased levels of nuclear beta-catenin, c-Myc, and cyclin D1 in the dorsolateral prostates of TRAMP mice. Similar effects were noted in TRAMP mice with established tumors. Treatment of DU145 human prostate cancer cells with 10 and 20 micromol/L apigenin also increased protein levels of E-cadherin by 27% to 74%, inhibited nuclear translocation of beta-catenin and its retention in the cytoplasm, and decreased c-Myc and cyclin D1 levels, an effect similar to the exposure of cells to beta-catenin small interfering RNA. Our results indicate that apigenin effectively suppressed prostate carcinogenesis in TRAMP mice, at least in part, by blocking beta-catenin signaling.
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PMID:Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. 1763 4

Epidemiological studies have demonstrated that people who eat more fruits and vegetables (rich in carotenoids) and people who have higher serum beta-carotene (BC) levels have a lower risk of cancer, particularly lung cancer. However, the two main human intervention studies of BC supplementation (the ATBC and the CARET trials) revealed an increased risk of lung cancer among smokers and asbestos workers. Previous studies carried out in the ferret have reported that BC effects are related to dose. Here, we treated ferrets with two concentrations of oral BC (0.8 and 3.2 mg/kg body weight per day) for 6 months, using BC in a formulation also containing dl-alpha-tocopherol and ascorbyl palmitate. The effect of the smoke-derived carcinogenic agent benzo[a]pyrene (BP), with or without low-dose BC, was also analysed. We determined the protein levels and mRNA expression levels of activator protein 1 (c-Jun and c-Fos), c-Myc, cyclin D1, proliferating cellular nuclear antigen and retinoic acid receptor beta. We did not find higher levels of cell proliferation markers in the lung of ferrets treated with BC or signals of squamous metaplasia lesions either. On the other hand, although no evident signals of pulmonary carcinogenesis were observed in animals exposed to BP, BC supplementation in these animals may prevent against excess cell proliferation, since this reestablishes Jun protein and cyclin D1 mRNA levels in the lung of BP-exposed animals. In summary, these results show that the combination of BC with alpha-tocopherol and ascorbyl palmitate does not induce pro-oxidant effects in the lung of ferrets.
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PMID:Effects of 6-month daily supplementation with oral beta-carotene in combination or not with benzo[a]pyrene on cell-cycle markers in the lung of ferrets. 1765 58

MAP17 is a non-glycosylated membrane-associated protein that has been shown to be over-expressed in human carcinomas, suggesting a possible role of this protein in tumorigenesis. However, very little is known about the molecular mechanism mediating the possible tumor promoting properties of MAP17. To analyze the effect of MAP17 on cell survival, we used Rat1 fibroblasts model where Myc over-expression promotes apoptosis in low serum conditions. In the present work, we report that over-expression of MAP17 protects Rat1a fibroblasts from Myc-induced apoptosis through reactive oxygen species (ROS)-mediated activation of the PI3K/AKT signaling pathway. MAP17-mediated survival was associated with absence of Bax translocation to the mitochondria and reduced caspase-3 activation. We show that a fraction of PTEN undergoes oxidation in MAP17-over-expressing cells. Furthermore, activation of AKT by MAP17 as measured by Thr308 phosphorylation was independent of PI3K activity. Importantly, modulation of ROS by antioxidant treatment prevented activation of AKT, restoring the level of apoptosis in serum-starved Rat1/c-Myc fibroblasts. Finally, over-expression of a dominant-negative mutant of AKT in MAP17-expressing clones makes them sensitive to serum depletion. Our data indicate that MAP17 protein activates AKT through ROS and this is determinant to confer resistance to Myc-induced apoptosis in the absence of serum.
Carcinogenesis 2007 Dec
PMID:MAP17 inhibits Myc-induced apoptosis through PI3K/AKT pathway activation. 1767 38

Astrocyte elevated gene-1 (AEG-1) displays oncogenic properties. Its expression is elevated in diverse neoplastic states and it cooperates with Ha-ras to promote cellular transformation. Overexpression of AEG-1 augments invasion and anchorage-independent growth of transformed cells, while AEG-1 siRNA inhibits Ha-ras-mediated colony formation, supporting a potential functional role in tumorigenesis. Additionally, oncogenic Ha-ras induces AEG-1 expression through the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In the present study, we investigated whether AEG-1 could induce serum-independent cell growth, another property of oncogenes. Overexpression of AEG-1 inhibited serum starvation-induced apoptosis through activation of PI3K-Akt signaling, one of the effector pathways induced by activated Ras. AEG-1 also affected the phosphorylation state of Akt substrates that are implicated in apoptosis suppression, including glycogen synthase kinase 3beta, c-Myc, murine double minute 2, p53, p21/mda-6 and Bad. Additionally, AEG-1 blocked the activity of serum starvation-induced caspases. Taken together, these observations provide evidence that AEG-1 is an oncogene cooperating with Ha-ras as well as functioning as a downstream target gene of Ha-ras and may perform a central role in Ha-ras-mediated carcinogenesis. Activation of survival pathways may be one mechanism by which AEG-1 exerts its oncogenic properties.
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PMID:Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. 1770 8

The INK4 family members p16(INK4a) and p15(INK4b) negatively regulate cell cycle progression by inhibition of cyclin-dependent kinase (CDK) 4/6. Loss of p16(INK4a) functional activity is frequently observed in tumor cells, and is thought to be one of the primary causes of carcinogenesis. In contrast, despite the biochemical similarity to p16(INK4a), the frequency of defects in p15(INK4b) was found to be lower than in p16(INK4a), suggesting that p15(INK4b)-inductive agents may be useful for tumor suppression. Here we report the discovery of a novel pyrido-pyrimidine derivative, JTP-70902, which exhibits p15(INK4b)-inducing activity in p16(INK4a)-inactivated human colon cancer HT-29 cells. JTP-70902 also induced another CDK-inhibitor, p27(KIP1), and downregulated the expression of c-Myc and cyclin D1, resulting in G(1) cell cycle arrest. MEK1/2 was identified by compound-immobilized affinity chromatography as the molecular target of JTP-70902, and this was further confirmed by the inhibitory activity of JTP-70902 against MEK1/2 in kinase assays. JTP-70902 suppressed the growth of most colorectal and some other cancer cell lines in vitro, and showed antitumor activity in an HT-29 xenograft model. However, JTP-70902 did not inhibit the growth of COLO320 DM cells; in these, constitutive extracellular signal-regulated kinase phosphorylation was not detected, and neither p15(INK4b) nor p27(KIP1) induction was observed. Moreover, p15(INK4b)-deficient mouse embryonic fibroblasts were found to be more resistant to the growth-inhibitory effect of JTP-70902 than wild-type mouse embryonic fibroblasts. These findings suggest that JTP-70902 restores CDK inhibitor-mediated cell cycle control by inhibiting MEK1/2 and exerts a potent antitumor effect.
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PMID:Identification of JTP-70902, a p15(INK4b)-inductive compound, as a novel MEK1/2 inhibitor. 1778 72


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