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)

To study the status of oxidative DNA damage in Helicobacter pylori infection in more detail, we examined oxidative DNA damage to individual genes by determining the loss of PCR product of a targeted gene before and after gastric mucosal DNA was treated with 8-hydroxyguanine glycosylase, which cleaves DNA at the 8-hydroxyguanine residues. The results showed that, of the 5 genes tested, p53, insulin-like growth factor II receptor and transforming growth factor-beta receptor type II showed significant oxidative DNA damage in H. pylori-positive tissues and that the BAX and beta-ACTIN genes were relatively undamaged. These results suggest that in H. pylori infection, oxidative DNA damage does not occur homogeneously throughout the genomic DNA but, rather, in a gene-specific manner. We conclude that the progressive accumulation of preferential oxidative DNA damage in certain genes, such as p53, likely contributes to gastric carcinogenesis.
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PMID:Gene-specific oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. 1199 37

Cyclooxygenase-2 (COX-2) expression appears to be important in colorectal carcinogenesis. Elevated COX-2 expression and activity have been observed in several different transformed cell types. Prior studies implicating involvement of the Ras oncogene and growth factors on COX-2 expression were largely derived from rat small intestinal cell lines. We have investigated whether mouse colonocyte COX-2 levels are regulated by oncogenic Ras or transforming growth factor-beta(1) (TGF-beta(1)), and whether these factors also serve to regulate cellular invasiveness. Young adult mouse colonocyte cells are colonocytes derived from the "Immortomouse" and immortalized by the SV40 large T antigen. Young adult mouse colonocyte Ras cells were derived by transfection of young adult mouse colonocyte cells with oncogenic Ha-Ras and are known to be tumorigenic. We found that the induction of COX-2 and eicosanoid release were augmented in the presence of activated Ras and that TGF-beta(1) caused a further increase in COX-2 in the Ras-transformed mouse colonocytes. Increased COX-2 expression was correlated with increased release of prostaglandins E(2) and I(2). Activated Ras and TGF-beta increased the invasiveness of the young adult mouse colonocyte cells, but treatment with a COX-2 inhibitor did not inhibit invasiveness. Thus we found that transforming growth factor-beta collaborates to increase COX-2 expression, protaglandin release, and invasiveness in mouse colonocytes, but the increased COX-2 activity does not appear to contribute to the invasive response.
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PMID:Induction of cyclooxygenase-2 and invasiveness by transforming growth factor-beta(1) in immortalized mouse colonocytes expressing oncogenic Ras. 1202 79

The gene for the transducer of transforming growth factor-beta/bone morphogenetic protein signalling SMAD4, a potential suppressor of colorectal carcinogenesis, is located at the chromosomal region 18q21. In order to evaluate the clinical relevance of SMAD4 deletion, gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 colorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy. Patients with normal SMAD4 diploidy turned out to have a three-fold higher benefit of 5-fluorouracil-based adjuvant chemotherapy with a border line significance (overall survival: 3.23, P=0.056; disease-free survival: 2.89, P=0.045). These data are consistent with the previous observation that patients whose cancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy. Moreover, these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion, thereby suggesting SMAD4 as a predictive marker in colorectal cancer. This data also indicate that integrity of this component of the transforming growth factor-beta/bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with colorectal cancer.
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PMID:SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer. 1223 73

Bone morphogenetic proteins (BMP) are members of the transforming growth factor-beta superfamily regulating a large variety of biologic responses in many different cells and tissues during embryonic development and postnatal life. BMP exert their biologic effects via binding to two types of serine/threonine kinase BMP receptors, activation of which leads to phosphorylation and translocation into the nucleus of intracellular signaling molecules, including Smad1, Smad5, and Smad8 ("canonical" BMP signaling pathway). BMP effects are also mediated by activation of the mitogen-activated protein (MAP) kinase pathway ("noncanonical" BMP Signaling pathway). BMP activity is regulated by diffusible BMP antagonists that prevent BMP interactions with BMP receptors thus modulating BMP effects in tissues. During skin development, BMPs its receptors and antagonists show stringent spatiotemporal expressions patterns to achieve proper regulation of cell proliferation and differentiation in the epidermis and in the hair follicle. In normal postnatal skin, BMP are involved in the control of epidermal homeostasis, hair follicle growth, and melanogenesis. Furthermore, BMP are implicated in a variety of pathobiologic processes in skin, including wound healing, psoriasis, and carcinogenesis. Therefore, BMPs represent new important players in the molecular network regulating homeostasis in normal and diseased skin. Pharmacologic modulation of BMP signaling may be used as a new approach for managing skin and hair disorders.
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PMID:Bone morphogenetic proteins and their antagonists in skin and hair follicle biology. 1253 96

The molecular genetics underlying thyroid carcinogenesis is not well understood. We have recently created a mutant mouse by targeting a mutation (PV) into the thyroid hormone receptor beta gene (TRbetaPV mouse). TRbetaPV/PV mice spontaneously develop follicular thyroid carcinoma through pathological progression of hyperplasia, capsular and vascular invasion, anaplasia and eventually metastasis to distant organs. TRbetaPV/PV mice provide an unusual opportunity to study the alterations in gene regulation that occur during thyroid carcinogenesis. To this end, we profiled the genomic changes in the thyroids of TRbetaPV/PV mice at 6 months of age, at which time metastasis had begun. From arrays of 20 000 mouse cDNAs, 185 genes were up-regulated (2-17-fold) and 92 were down-regulated (2-20-fold). Functional clustering of named genes with reported functions (100 genes) indicated that approximately 39% of these genes were tumor-, metastasis/invasion- and cell-cycle-related. Among the activated tumor-related genes identified, cyclin D1, pituitary tumor transforming gene-1, cathespin D and transforming growth factor alpha were also found to over-express in human thyroid cancers. Analyses of the gene profiles suggested that the signaling pathways mediated by thyrotropin, peptide growth factors, transforming growth factor-beta, tumor necrosis factor-alpha and nuclear factor-kappaB were activated, whereas pathways mediated by peroxisome proliferation activated receptor gamma were repressed. These results indicate that complex alterations of multiple signaling pathways contribute to thyroid carcinogenesis. The critical genes associated with thyroid follicular carcinogenesis uncovered in the present study could serve as signature genes for diagnostic purposes, as well as for possible therapeutic targets.
Carcinogenesis 2003 Sep
PMID:Alterations in genomic profiles during tumor progression in a mouse model of follicular thyroid carcinoma. 1286 18

Loss of the tumor suppressive effect of transforming growth factor-beta (TGF-beta) has been commonly found at later stages in carcinogenic progression. Although the genes encoding TGF-beta receptors and Smads have been found genetically altered in certain human cancers, no mutation in Smad3 has been observed. Therefore, suppression of Smad3 expression may mediate key oncogenic properties of TGF-beta. First, we observed that 37.5% of human gastric cancer tissues showed low to undetectable levels of Smad3 and that in nine human gastric cancer cell lines examined, two showed deficient Smad3 expression. Introduction of Smad3 into human gastric cancer cells that did not express Smad3, restored TGF-beta responsiveness: induction of p21 and p15 gene expression, and growth inhibition in response to TGF-beta. Furthermore, these Smad3-expressing cells showed markedly decreased and delayed tumorigenicity in vivo. These findings suggest that Smad3 expression may have a critical role in tumor suppression in the early stages of gastric carcinogenesis.
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PMID:Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer. 1464 20

Smad4 is a tumour suppressor gene predominantly involved in gastrointestinal carcinogenesis. Loss of Smad4 is considered to be a genetically late step and occurs in up to 30% of metastatic colorectal carcinomas. Smad4, originally characterized as an intracellular transmitter of transforming growth factor-beta (TGF-beta) signals, is a transcriptional co-modulator capable of integrating cellular responses to multiple signalling cascades. Thus, there are many Smad4 target genes and they are presumably strongly context-dependent. It was recently shown that re-expression of Smad4 in Smad4-deficient SW480 human colon carcinoma cells restored epithelioid morphology and induced P-cadherin and E-cadherin transcription. The cadherins are key players in cell-cell adhesion connecting adjacent cells via the cadherin-catenin adhesion complex. Frequent loss of E-cadherin expression in human cancers has been a long-standing observation, but the underlying mechanisms are not yet fully understood. To assess the role of Smad4 in E-cadherin regulation in colorectal carcinogenesis further, the present study has analysed Smad4 and E-cadherin RNA and protein expression in colorectal carcinoma cell lines and in 51 late-stage colorectal carcinomas. In primary tumours, loss of Smad4 expression correlated highly significantly with loss of E-cadherin expression, thus providing further evidence for involvement of the tumour suppressor Smad4 in the control of expression of the tumour and invasion suppressor E-cadherin.
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PMID:Loss of Smad4 correlates with loss of the invasion suppressor E-cadherin in advanced colorectal carcinomas. 1509 68

Since its discovery in the early 1980s, transforming growth factor-beta (TGF-beta) has emerged as a family of growth factors involved in essential physiological processes, including embryonic development, differentiation, tissue repair and cell growth control. Knockout experiments for the three mammalian isoforms of TGF-betas in mice have demonstrated their importance in regulating inflammation and tissue repair. Also, TGF-beta has been implicated in the pathogenesis of human diseases, including tissue fibrosis and carcinogenesis where, in the latter case, it may exert both tumor suppressor and pro-oncogenic activities depending on the stage of the tumor. Cellular signaling by TGF-beta family members is initiated by the assembly of specific cell surface serine/threonine kinase type receptors that activate transcription factors of the Smad family.
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PMID:Mammalian transforming growth factor-betas: Smad signaling and physio-pathological roles. 1510 63

Cervical carcinoma is a human papilloma virus (HPV)-related immunogenic type of malignancy, in which escape of the tumor from the hosts' immune response is thought to play an important role in carcinogenesis. The multifunctional cytokine transforming growth factor-beta(1) (TGF-beta(1)) is involved in immunosuppression, stroma and extracellular matrix formation and controlling (epithelial) cell growth. The plasminogen activating (PA) system plays a key role in the cascade of tumor-associated proteolysis leading to extracellular matrix degradation and stromal invasion. Changes in expression of components of this system, including plasminogen activator inhibitor-1 (PAI-1), have been associated with poor prognosis in a variety of solid tumors. The present study was undertaken to assess the role of both components on relapse, survival and other clinicopathologic parameters in cervical cancer. The expression of TGF-beta(1) mRNA in 108 paraffin-embedded cervical carcinomas was detected by mRNA in situ hybridization. Immunohistochemistry was used to investigate the expression of PAI-1 protein. The presence of cytoplasmatic TGF-beta(1) mRNA in tumor cells was not significantly correlated with the other clinicopathologic parameters investigated or with a worse (disease-free) survival. Expression of the PAI-1 protein in tumor cells was strongly correlated with worse overall and disease-free survival, in addition to well-known prognostic parameters such as lymph node metastasis, depth of tumor infiltration, tumor size and vasoinvasion. In the multivariate analysis, PAI-1 turned out to be a strong independent prognostic factor. In a subgroup of patients without lymph node metastases, PAI-1 was predictive for worse survival and relapse of disease, too. Our results show that the (enhanced) expression of PAI-1 by carcinoma cells is correlated with worse (overall and disease-free) survival of patients with cancer of the uterine cervix. The expression of TGF-beta(1) in itself is not associated with worse survival in these patients. Although simultaneous presence of the 2 factors was observed in all tumors, induction of PAI-1 by TGF-beta(1) could not be demonstrated in our group of cervical carcinomas.
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PMID:Prognostic relevance of TGF-beta1 and PAI-1 in cervical cancer. 1538 52

Retinoic acid and transforming growth factor-beta (TGF-beta) affect differentiation, proliferation and carcinogenesis of epithelial cells. The effect of both compounds on the proliferation of cells of the hormone sensitive human breast cancer cell line (ER+) MCF-7 was assessed in the presence of estradiol and tamoxifen. The assay was based on [3H]thymidine incorporation and the proliferative activity of PCNA- and Ki 67-positive cells. The apoptotic index and expression of the Bcl-2 and p53 antigens in MCF-7 cells were also determined. Exogenous TGF-beta1 added to the cell culture showed antiproliferative activity within the concentration range of 0.003-30 ng/ml. Irrespective of TGF-beta1 concentrations, a marked reduction in the stimulatory action of estradiol (10(-9) and 10(-8) M) was observed whereas in combination with tamoxifen (10(-7) and 10(-6) M) only 30 ng/ml TGF-beta1 caused a statistically significant reduction to approximately 30% of the proliferative cells. In further experiments we examined the effect of exposure of breast cancer cells to retinoids in combination with TGF-beta1. The incorporation of [3H]thymidine into MCF-7 cells was inhibited to 52 +/- 19% (control =100%) by 3 ng/ml TGF-beta1, and this dose was used throughout. It was found that addition of TGF-beta1 and isotretinoin to the culture did not decrease proliferation, while TGF-beta1 and tretinoin at low concentrations (3 x 10(-8) and 3 x 10(-7) M) reduced the percentage of proliferating cells by approximately 30% (67+/-8% and 67+/-5%, P<0.05 compared to values in the tretinoin group). Both retinoids also led to a statistically significant decrease in the stimulatory effect of 10(-9) M estradiol, attenuated by TGF-beta1. In addition, the retinoids in combination with TGF-beta1 and tamoxifen (10(-6) M) caused a further reduction in the percentage of proliferating cells. Immunocytochemical analysis showed that all the examined compounds gave a statistically significant reduction in the percentage of cells with a positive reaction to PCNA and Ki 67 antigen. TGF-beta1, isotretinoin and tretinoin added to the culture resulted in the lowest percentage of PCNA positive cells. However, the lowest fraction of Ki 67 positive cells was observed after addition of isotretinoin. The obtained results also confirm the fact that the well-known regulatory proteins Bcl-2 and p53 play an important role in the regulation of apoptosis in the MCF-7 cell line, with lowered Bcl-2 expression accompanying easier apoptotic induction. The majority of the examined compounds act via the p53 pathway although some bypass this important proapoptotic factor.
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PMID:Can transforming growth factor-beta1 and retinoids modify the activity of estradiol and antiestrogens in MCF-7 breast cancer cells?. 1544 35


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