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)

The inappropriate activation of protein-tyrosine kinases (PTKs) has been associated with initiation and progression of several types of human cancers. We therefore postulated that immortalization by DNA tumor viruses results in the induction of PTKs fundamental to these processes. An RT-PCR-based screen was thus used to identify PTKs that were abundantly expressed in HPV-18-immortalized epithelial cells and HPV-containing carcinoma cell lines. One of the genes isolated in this screen was the focal adhesion kinase (FAK; pp125FAK), a cytoplasmic protein kinase that is activated in v-src transformed cells or by stimulation with mitogenic polypeptides. FAK also becomes catalytically active upon integrin engagement with extracellular matrix proteins, such as fibronectin. We found that FAK expression and activity were significantly elevated in HPV-18 E6/E7-immortalized human genital epithelial cells relative to their primary cell counterparts. Protein expression and tyrosine phosphorylation of the putative FAK substrate, paxillin, were also notably increased upon HPV-18 immortalization of genital epithelial cells and in HPV-containing cervical carcinoma cell lines. Most significantly, these cells expressed markedly higher levels of both intracellular and extracellular fibronectin, thus providing a mechanism for activation of FAK and increased tyrosine phosphorylation of paxillin. These findings suggest a role for the integrin/FAK-mediated signaling pathway in cervical carcinogenesis and represent one of the first demonstrations of a tyrosine kinase whose activity is elevated following viral immortalization.
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PMID:Activation of the focal adhesion kinase signal transduction pathway in cervical carcinoma cell lines and human genital epithelial cells immortalized with human papillomavirus type 18. 923 61

Loss of attachment may induce apoptosis in epithelial cells, but it is unclear whether substrate adhesion modulates apoptosis triggered by genotoxic agents such as ultraviolet radiation (UV). To investigate this issue, we plated neonatal human keratinocytes on different substrates and irradiated them with UVB. DNA strand breaks were nick-labeled to identify apoptotic nuclei. Keratinocytes grown in monolayers were less susceptible to UV-induced apoptosis than were cells freshly seeded on glass (ED50 2130 +/- 96 J per m2, mean +/- SD, versus 131 +/- 96 J per m2, mean +/- SD, respectively). This phenomenon depended on differences in integrin-mediated adhesion, because blocking of integrin beta1 with a monoclonal antibody increased sensitivity of keratinocyte monolayers to UV and an increase in beta1 integrin receptor occupancy by plating on fibronectin, type IV collagen, or keratinocyte-derived extracellular matrix diminished the UV-dependent apoptosis. Down-regulation of p53 with an anti-sense oligonucleotide did not affect apoptosis in glass-plated keratinocytes but effectively suppressed apoptosis in keratinocytes adhering via beta1 integrin. Thus, in addition to the known p53-dependent pathway, UV was able to induce a p53-independent apoptosis that could be blocked by integrin-mediated cell attachment (the integrin-sensitive pathway). The susceptibility to the p53-dependent apoptosis, but not to the integrin-sensitive process, varied among keratinocytes of different clonogenic potential: transit amplifying cells > stem cells > terminally differentiated cells. The p53-independent integrin-sensitive apoptotic pathway may provide an additional mechanism counteracting UV carcinogenesis in the skin.
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PMID:Two pathways for induction of apoptosis by ultraviolet radiation in cultured human keratinocytes. 924 2

Cytoskeleton not only controls cell morphology but also regulates cell growth, migration, differentiation, and gene expression, events which are fundamental to embryogenesis, carcinogenesis, and wound healing. We have recently reported that reorganization of cytoskeleton induces expression of mRNA for transforming growth factor-beta 1 (TGF-beta 1), collagenase, and tissue inhibitor of metalloproteinase-I (TIMP-I) in dermal fibroblasts. In this report we have examined the role of gene transcription in this induction. As judged by nuclear run-on assay, trypsin, EGTA (ethylene glycol-bis (beta-aminoethyl ether) N, N, N', N', tetra-acetic acid), or cytochalasin C (Chs) increased the rate of transcription of the TGF-beta 1 gene by 2.0, 2.7, and 1.6 fold, respectively, and of the collagenase gene by 5.3, 6.2, and 3.3 fold. The rate of transcription of the TIMP-I gene was increased by trypsin (4.3 fold) or EGTA (3.8 fold) but unaffected by Chs. Cytochalasin induced an increase in the rate of transcription of procollagen I (alpha 1), procollagen I (alpha 2), and fibronectin genes by 1.4, 1.5, and 1.9 fold respectively, while trypsinization or EGTA treatment had no or little effects on these gene. Since transcription of the TGF-beta 1 gene is believed to be largely governed by the activating protein 1 (AP1) complex, we also examined the expression of mRNA for c-fos and c-jun protoon-coproteins. Trypsinization induced rapid (within 30 min) and transient expression of c-fos mRNA. A 2.4 fold increase in c-jun mRNA was apparent after 4 hr and persisted for at least 24 hr. Actinomycin D (Act D) suppressed the induction of TGF-beta 1 mRNA by Chs but had less effect on the TGF-beta 1 mRNA in trypsinized cells which had been replated for 4 hr, suggesting that the half life of TGF-beta 1 mRNA is reduced in cells with a disassembled cytoskeleton. Simultaneous treatment with Chs and cycloheximide (Cxm) resulted in a superinduction of TGF-beta 1 mRNA by 88 +/- 23% (n = 4, P < 0.05), which was abrogated by preexposure to Act D. In contrast, the induction of collagenase mRNA by Chs was totally blocked by Cxm, indicating that the Cxm-mediated superinduction is selective and that protein synthesis is required for induction of this mRNA. Our results suggest that the activities of genes for proteins involved in the structure (Type I collagen and fibronectin), turnover (collagenase and TIMP-1) and regulation (TGF-beta 1) of extracellular matrix (ECM), are all governed at least in part by the status of the cytoskeleton. Since the cytoskeleton is reorganized during cell division, migration, and differentiation, these results may have implications for the regulation of ECM during such processes as embryogenesis, carcinogenesis, and wound healing.
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PMID:Cytoskeleton regulates expression of genes for transforming growth factor-beta 1 and extracellular matrix proteins in dermal fibroblasts. 925 40

CC10 is infrequently expressed in non-small cell lung cancer cell lines, despite being abundantly produced by progenitor cells for normal and neoplastic airway epithelium. We overexpressed CC10 cDNA in the non-small cell lung cancer cell line A549 to determine its effect on the neoplastic phenotype. A549 cells transfected with CC10 demonstrated a marked reduction in invasiveness that was paralleled by diminished 92-kDa and absent 72-kDa metalloproteinase activity by zymography. Western analysis revealed the near absence of the corresponding matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in the CC10-transfected cell lines, but not in the vector-transfected cell lines. The CC10-transfected cell lines also demonstrated decreased adhesiveness to fibronectin compared with the controls. CC10 expression was associated with decreased anchorage-independent growth but not with decreased anchorage-dependent growth. These data suggest that loss of CC10 may contribute to carcinogenesis, because CC10 antagonizes the neoplastic phenotype.
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PMID:Overexpression of CC10 modifies neoplastic potential in lung cancer cells. 966 66

Decorin is a member of the small leucine-rich proteoglycan (SLRP) gene family that has recently become a focus in various areas of cancer research. The decorin protein consists of a core protein and a covalently linked glycosaminoglycan chain. Decorin binds to collagens type I, II and IV in vivo and promotes the formation of fibers with increased stability and changes in solubility. Further, the decorin core protein binds to growth factors, including transforming growth factor-beta (TGF-beta), to other intercellular matrix molecules such as fibronectin and thrombospondin, and to the decorin endocytosis receptor. Decorin may directly interfere with the cell cycle via the induction of p21WAF1/CIP1 (p21), a potent inhibitor of cyclin-dependent kinases (CDKs). Here, we discuss interactions of decorin with TGF-beta and with p21, both of which are relevant to carcinogenesis and tumor progression. TGF-beta is released by tumors of various histogenetic origins and promotes immunosuppression in the host and tumor immune escape by induction of growth arrest and apoptosis in immune cells, by downregulation of MHC II antigen expression and by changes in the cytokine release profiles of immune and tumor cells. Moreover, TGF-beta may modulate tumor growth in an autocrine and paracrine fashion, may mediate drug resistance, and may facilitate tumor angiogenesis. Decorin binds to TGF-beta, thus inhibiting its bioactivity, and is a direct or indirect negative modulator of TGF-beta synthesis. Ectopic expression of decorin results in the regression of rat C6 gliomas, an antineoplastic effect attributed to the reversal of TGF-beta-induced immunosuppression. On the other hand, de novo expression of decorin in colon cancer cells and some other tumor cells, even though not in glioma cells, results in an upregulation of p21 expression and a cell cycle arrest, presumably in a TGF-beta-independent manner. Decorin expression is downregulated in many tumors but upregulated in the peritumoral stroma. By virtue of its growth regulatory and immunomodulatory properties, decorin promises to become a novel target for the experimental therapy of human cancers.
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PMID:Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. 1038 66

Metallothionein (MT) is a low molecular weight, cysteine-rich, zinc-binding protein that may have a function in cellular repair processes, growth and differentiation. Using a monoclonal antibody (E9) to metallothionein, we investigated the immunohistochemical expression of MT in routinely fixed and paraffin-embedded tissue from 98 cases of female breast carcinomas. The MT expression was studied in comparison with the expression of the basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, adhesion molecule CD44, p53 protein, the pRb, c-erbB-2 oncoprotein, EGFR, stromelysin-1, proliferation indices (Ki-67, PCNA), steroid receptor content as well as with other conventional clinicopathological parameters of breast cancer. Strong MT expression was observed in the majority of tumour cells in 18.4% of tumours, focal MT positivity in 13.3% and almost complete lack of MT expression in 68.4% of cases (mean value 33.36 +/- 26.36). The MT expression in carcinoma cells was strongly associated with the DCIS component of the tumour (p < 0.0001). High values of MT were correlated with low steroid receptor status (p = 0.08 for ER receptor and p = 0.019 for PgR receptor content). MT positive cases were correlated with stromelysin-1 expression (p = 0.059) and cathepsin D (p = 0.058). These findings suggest that MT expression is characteristic of the early phase of breast carcinogenesis, possibly regulated by hormones, and could be a new potential prognostic marker in breast cancer.
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PMID:Immunohistochemical localization of metallothionein in human breast cancer in comparison with cathepsin D, stromelysin-1, CD44, extracellular matrix components, P53, Rb, C-erbB-2, EGFR, steroid receptor content and proliferation. 1047 Jan 61

Mammary epithelial cell differentiation depends on lactogenic hormones, growth factors, and cell-cell and cell-substrate interactions, all of which modulate transcription factors essential for milk protein gene expression. The CCAAT/enhancer binding protein (C/EBP) family and the signal transducer and activator of transcription 5 (Stat5) have been implicated in mammary epithelial cell growth and differentiation. We have investigated the effects of extracellular matrix components and lactogenic hormones on C/EBP and Stat5 activity. In the mammary gland, tenascin is expressed mainly during embryogenesis and carcinogenesis and in cell culture tenascin downregulates beta-casein gene expression. In HC11 mammary cells, we found that tenascin, but not laminin or fibronectin, specifically downregulated C/EBPalpha levels but had no effect on Stat5 amount or DNA binding activity. Furthermore, we found that the lactogenic hormones, glucocorticoids, prolactin, and insulin, had no effect on C/EBPalpha and C/EBPbeta protein levels but downregulated the DNA binding activity of the transcriptional repressor C/EBPbetaLIP. Thus, C/EBPalpha and beta are regulated by tenascin and lactogenic hormones in mammary epithelial cells.
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PMID:Lactogenic hormones and tenascin-C regulate C/EBPalpha and beta in mammary epithelial cells. 1064 37

Oncogenes and N-acetylglucosaminyltransferase (GnT-V) are both commonly associated with carcinogenesis and metastasis. In order to elucidate the relationship between oncogenes and GnT-V, two oncogenes, H-ras and v-sis/PDGF (platelet-derived growth factor), were selected, and the effects of their overexpression on GnT-V in 7721 human hepatocarcinoma cells were investigated. The results showed that the over expression of H-ras or v-sis/PDGF-B up-regulated the activities of GnT-V to various degrees in the transfected cells. In H-ras- and PDGF-B-overexpressing cells, the activity of GnT-V was up-regulated to double the normal value. The transient expression of v-sis, which produces a protein almost identical to PDGF-B, stimulated the GnT-V activity by 80.3%, and the effect was more pronounced (increased by 182.5%) in 7721 cells with stable expression of v-sis. The stimulating effect was entirely abolished by treatment with PDGF-B antibody. The staining of asparagine-linked glycans (N-glycans) in the H-ras- and v-sis-overexpressing 7721 cells was intensified when horseradish peroxidase-labeled leucoagglutinating phytohemogglutinin was used as a probe, indicating the increased content of beta1,6GlcNAc branching on the N-glycans. The enhancement of GnT-V mRNA expression was also observed in H-ras- and v-sis- overexpressing cells, indicating that H-ras and v-sis regulated GnT-V via the transcription of GnT-V mRNA and the synthesis of GnT-V protein. The cells overexpressing H-ras and v-sis displayed some changes in metastasis-related phenotypes, including acceleration of cell growth, decline of cell adhesion to fibronectin, and an increase of cell adhesion to laminin, as well as increased invasiveness through Matrigel. These results indicated that the alteration of cell adhesion and invasion induced by oncogenes is closely related to the up-regulation of GnT-V activity and its product, beta1,6GlcNAc branching in N-glycans on the cell surface.
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PMID:Effects of H-ras and v-sis overexpression on N-acetylglucosaminyltransferase V and metastasis-related phenotypes in human hepatocarcinoma cells. 1081 61

Alterations of basement membrane (BM) in di-isopropanolnitrosamine (DIPN)-induced carcinogenesis of the rat thyroid gland were examined by means of immunohistochemical localization of collagen type IV (CN-IV), laminin (LN), and fibronectin (FN) in prenodular and nodular thyroid lesions, correlating with the morphogenesis and proliferative activity of these lesions. Adult male rats of the Wistar strain were injected s.c. in the back with DIPN, and the thyroid glands were removed at the 15th and 30th week of treatment. Each of 133 thyroid lesions was histochemically analyzed. The follicular epithelial BM as revealed by CN-IV and LN was discontinued or completely lost during the progression of thyroid lesions from pre-nodular to nodular lesions and finally overt carcinomas. At the same time, the BM of vascular endothelial cells demonstrated a loss of dense capillary networks of follicles, a sinusoidal dilatation and, predominantly in carcinomas, development of interstitial-type blood vessels. However, FN, which was hardly stained in the normal thyroid tissue, was remarkably deposited in the interstitium of invasive carcinomas. These observations strongly suggested that alterations of BM structure play a key role in the morphogenesis of rat thyroid tumors, and that the expression of FN is an important step in the invasive growth of thyroid tumors.
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PMID:Alterations of basement membrane in di-isopropanolnitrosamine-induced carcinogenesis of the rat thyroid gland: an immunohistochemical study. 1091 75

Former East German uranium miners who are known to have been exposed to radon are estimated to be at high risk for lung carcinogenesis. Among these miners over 200 occupationally caused lung cancer cases are expected to occur each year, resulting in a total of 7,000-24,000 excess lung cancer cases in the coming years. It is still unknown whether there is a correlation between biomarkers and the exposure of the uranium miners to ionizing radiation that might enable us to trace those miners with high lung cancer risk. The primary aim of this pilot study was to test the possibility of performing a biomarker study in this unique cohort of former uranium miners in spite of several limitations that had to be taken into consideration when comparing them with healthy controls, such as old age, age-dependent diseases and potential confounding artefacts from dissimilar smoking patterns. The second aim was to test a range of biomarkers for DNA damage and inflammation in leukocytes and bronchoalveolar fluid for their ability to detect biological effects. In this cohort of miners we found an increased frequency of chromosomal aberrations in blood lymphocytes and an increased prevalence of both fibronectin and tumour necrosis factor alpha in the bronchoalveolar fluid.
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PMID:Biomarkers of genetic damage and inflammation in blood and bronchoalveolar lavage fluid among former German uranium miners: a pilot study. 1120 Sep 71


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