Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Hepatocyte growth factor (HGF) is thought to play a role in cell motility and invasion. Matrix metalloproteinases (MMPs) have been implicated in invasion and metastasis of tumor cells. We have previously reported that the Ets-oncogene family transcription factor E1AF positively regulates transcription of MMP genes in transient expression assays and that overexpression of the E1AF gene confers an invasive phenotype on breast cancer cells. Here we examined the effect of HGF on E1AF and MMP gene expression in terms of the invasive potential of the oral squamous cell carcinoma cell line HSC3. HGF stimulated expression of the E1AF gene. The levels of MMP-1, -3 and -9 mRNAs increased in cells treated with HGF and correlated with E1AF upregulation. In contrast, no obvious upregulation of MMP-1 and -9 mRNA was observed in ASE1AFHSC3 cells transfected with the antisense E1AF expression vector into parental HSC3 cells. The wild-type MMP-9 gene promoter was activated by endogenous E1AF in HSC3 cells, and chloramphenicol acetyltransferase (CAT) activities increased when HGF was added to transfected cells. On the other hand, CAT activity was reduced to almost two-thirds of the wild-type activity when HSC3 cells were transfected with a CAT reporter plasmid driven by a mutant MMP-9 promoter lacking the Ets-binding site, and induction of CAT activity was not observed upon addition of HGF. Analysis of organotypic raft cultures revealed that HSC3 cells invaded and degraded collagen gel actively upon addition of HGF. These results suggest that HGF induces expression of the Ets-related E1AF transcription factor gene whose product in turn activates MMP genes and leads to oral cancer cell invasion.
Carcinogenesis 2000 Jun
PMID:Hepatocyte growth factor upregulates E1AF that induces oral squamous cell carcinoma cell invasion by activating matrix metalloproteinase genes. 1083 94

There are about 600 million betel quid (BQ) chewers in the world. BQ chewing is associated with increased incidence of oral cancer and submucous fibrosis. In this study, areca nut (AN) extract (200-800 microg/ml) induced the prostaglandin E(2) (PGE(2)) production by 1. 4-3.4-fold and 6-keto-PGF(1 alpha) production by 1.1-1.7-fold of gingival keratinocytes (GK), respectively, following 24 h of exposure. Exposure of GK to AN extract (>400 microg/ml) led to cell retraction and intracellular vacuoles formation. At concentrations of 800 and 1200 microg/ml, AN extract induced cell death at 21-24 and 32-52% as detected by MTT assay and cellular lactate dehydrogenase release, respectively. Interestingly, AN-induced morphological changes of GK are reversible. GK can still proliferate following exposure to AN extract. Cytotoxicity of AN extract cannot be inhibited by indomethacin (1 microM) and aspirin (50 microM), indicating that prostaglandin (PG) production is not the major factor responsible for AN cytotoxicity. PGE(2) exhibited little effect on the growth of GK at concentrations ranging from 100-1000 pg/ml. Stimulating GK production of PGs by AN extract could be due to induction of cyclooxygenase-2 (COX-2) mRNA expression and protein production. These results suggest that AN ingredients are critical in the pathogenesis of oral submucous fibrosis and oral cancer via their stimulatory effects on the PGs, COX-2 production and associated tissue inflammatory responses. AN cytotoxicity to GK is not directly mediated by COX-2 stimulation and PG production.
Carcinogenesis 2000 Jul
PMID:Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes. 1087 15

Oral cancer has increased recently in Australia, and overall survival rates have not improved in the past 30 years. Dentists are uniquely well placed to screen their patients at regular recall examinations and detect cancers or pre-cancerous lesions at an early curable stage. Although the major risk factors--tobacco smoking and alcohol abuse--have been identified, only a minority of patients at-risk will develop oral cancer. Molecular analysis has now detected an accumulation of genetic lesions in oral cancer, but the earliest molecular changes in the oral epithelium in the progression to malignancy in at-risk patients has not yet been determined. These changes could if known be exploited for screening purposes. How long human oral carcinogenesis takes to progress from the initiated cell to an invasive tumour, and whether molecular biology can be used to identify the minority of patients who will develop cancer from the large population exposed to the risk factors, are other important unanswered questions. p53 tumour suppressor gene mutations are the most frequently found genetic errors in oral cancer and the p53 gene is a likely target for tobacco and alcohol.
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PMID:A general review of the p53 gene and oral squamous cell carcinoma. 1089 14

This study identified that the carcinogenesis of hamster buccal pouch (HBP) induced by 7,12-dimethylbenz[a]anthracene (DMBA) was greatly enhanced (18 folds) by a combination treatment with Taiwanese betel quid (BQ) extract. A new cell line, HCDB-1, has been established from induced carcinomas. The cultured monolayer cells were epithelioid in shape with irregular nuclei. They demonstrated abundant cytokeratin and tonofilaments; however, ultrastructural well-organized desmosomes were lacking. The HCDB-1 cell exhibited population doubling in 19 h and was highly tumorigenic in nude mice. A C-->T transition at codon 141 (Ala to Val) of the p53 gene was detected in this cell. This mutation is equivalent to a specific temperature-sensitive mouse p53Ala135Val mutant that causes transformation by shifting to 37.5 degrees C. HCDB-1 is the first cell line established from the HBP model of oral carcinogenesis induced by DMBA/Taiwanese BQ extract. It might be valuable for exploring the molecular pathogenesis of oral cancer.
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PMID:Establishment and characterization of a cell line (HCDB-1) derived from a hamster buccal pouch carcinoma induced by DMBA and Taiwanese betel quid extract. 1094 46

Skp2 is a member of the F-box family of substrate-recognition subunits of SCF ubiquitin-protein ligase complexes that has been implicated in the ubiquitin-mediated degradation of several key regulators of mammalian G(1) progression, including the cyclin-dependent kinase inhibitor p27, a dosage-dependent tumor suppressor protein. In this study, we examined Skp2 and p27 protein expression by immunohistochemistry in normal oral epithelium and in different stages of malignant oral cancer progression, including dysplasia and oral squamous cell carcinoma. We found that increased levels of Skp2 protein are associated with reduced p27 in a subset of oral epithelial dysplasias and carcinomas compared with normal epithelial controls. Tumors with high Skp2 (>20% positive cells) expression invariably showed reduced or absent p27 and tumors with high p27 (>20% positive cells) expression rarely showed Skp2 positivity. Increased Skp2 protein levels were not always correlated with increased cell proliferation (assayed by Ki-67 staining), suggesting that alterations of Skp2 may contribute to the malignant phenotype without affecting proliferation. Skp2 protein overexpression may lead to accelerated p27 proteolysis and contribute to malignant progression from dysplasia to oral epithelial carcinoma. Moreover, we also demonstrate that Skp2 has oncogenic potential by showing that Skp2 cooperates with H-Ras(G12V) to malignantly transform primary rodent fibroblasts as scored by colony formation in soft agar and tumor formation in nude mice. The observations that Skp2 can mediate transformation and is up-regulated during oral epithelial carcinogenesis support a role for Skp2 as a protooncogene in human tumors.
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PMID:Skp2 is oncogenic and overexpressed in human cancers. 1130 91

Normal somatic cells terminate their replicative life span through a pathway leading to cellular senescence, which is triggered by activation of p53 and/or pRb in response to critically shortened telomere DNA. Potentially neoplastic cells must first overcome the senescence checkpoint mechanisms and subsequently activate telomerase to propagate indefinitely. Although telomerase activation is closely associated with cellular immortality, telomerase alone is not sufficient to warrant tumorigenicity. Environmental factors, including chemical carcinogens and viral infection, often contribute to aberrant changes leading to tumorigenic conversion of normal cells. Of particular importance in oral cancer development are tobacco-related chemical carcinogens and human papillomavirus (HPV) infection. To describe the molecular mechanisms by which these environmental factors facilitate the genesis of oral cancer, we first established an in vitro multistep oral carcinogenesis model by sequential exposure of normal human oral keratinocytes (NHOK) to "high risk" HPV and chemical carcinogens. Upon introduction of the HPV genome, the cells bypassed the senescence checkpoint and entered into an extended, but not immortal, life span during which telomere DNA continued to shorten. In a few immortal clones surviving beyond the crisis, we found a marked elevation of telomerase activity and stabilization of telomere length. Furthermore, the E6 and E7 oncoproteins of "high risk" HPV disrupted the cell cycle control and DNA repair in immortalized HOK, and enhanced mutation frequency resulting from genomic instability. However, HPV infection alone failed to give rise to a tumorigenic cell population, which required further exposure to chemical carcinogens in addition to HPV infection. Analysis of the data presented suggests that oral carcinogenesis is a series of discrete genetic alterations that result from a continued genotoxic challenge by environmental risk factors. Our in vitro model may be useful for investigators with interest in furthering our understanding of oral carcinogenesis.
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PMID:Conversion of normal to malignant phenotype: telomere shortening, telomerase activation, and genomic instability during immortalization of human oral keratinocytes. 1134 61

Topical application of 7,12-dimethylbenz(alpha)-anthracene induces tumors in the hamster cheek pouch. Telomerase activity is increased in the cancer tissues if compared to normal adjacent tissues in both human and hamster oral cancer. In order to achieve a probe and to investigate the putative role of telomerase in oral carcinogenesis using the hamster cheek pouch model, we have cloned the cDNA encoding the hamster telomerase catalytic subunit (hamTERT). The hamster TERT cDNA encoded 1128 amino acids and shared 64% amino acid identity with human TERT and 80% with murine TERT. As noted with human TERT which express several alternatively spliced mRNAs, we have also detected one alternatively spliced hamTERT mRNA in hamster cancer cells. Transient transfection of hamTERT cDNA in a retroviral expression vector reconstituted telomerase activity in the telomerase negative human lung fibroblast IMR90 cells.
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PMID:Cloning and expression of hamster telomerase catalytic subunit cDNA. 1140 53

Accumulation of mitochondrial DNA (mtDNA) mutations in human tissues has been associated with intrinsic aging and environmental insult. Recently, mtDNA mutations have been detected in various tumors, including head and neck tumors. However, the factors affecting the occurrence and accumulation of mtDNA deletions in tumor tissues are poorly understood. In Taiwan, betel quid chewing is a major risk factor for oral cancer. Using polymerase chain reaction (PCR) techniques, we examined large-scale deletions of mtDNA in 53 pairs of tumor and non-tumor oral tissues from the patients with or without betel quid chewing history. The results revealed that irrespective of the history of betel quid chewing, the incidences of the 4977bp deletion and other deletions of mtDNA were lower in the tumor portion as compared with the non-tumor portion. The average proportions of the 4977bp deleted mtDNA in the tumor tissues of the betel quid chewers and non-betel quid chewers were 13- and 5-fold, respectively, lower than those in the corresponding non-tumor tissues. Moreover, the average proportion of 4977bp deleted mtDNA was significantly higher (P<0.05) in the non-tumor oral tissues of the patients with betel quid chewing history than that of the patients without the history of betel quid chewing. These results suggest that betel quid chewing may increase mtDNA mutation in human oral tissues and that accumulation of mtDNA deletions and subsequent cytoplasmic segregation of these mutations during cell division could be an important contributor to the early phase of oral carcinogenesis.
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PMID:Accumulation of mitochondrial DNA deletions in human oral tissues -- effects of betel quid chewing and oral cancer. 1151 16

p53 mutations are etiologically associated with the development of oral squamous cell carcinomas (OSCCs) or are associated with exposure to specific carcinogens. In this study, we used PCR-single strand conformation polymorphism and DNA sequencing to analyze the conserved regions of the p53 gene (exons 5-9) in OSCC tumor specimens from 187 patients with varied histories of betel quid, tobacco and alcohol use. Ninety-one of the 187 OSCCs (48.66%) showed p53 gene mutations at exons 5-9. The incidence of p53 mutations was not associated with age, sex, TNM stage, status of cigarette smoking or betel quid chewing. However, alcohol drinkers exhibited a significantly higher incidence (57/101, 56.44%) of p53 mutations than non-users (39.53%, 34/86) (P = 0.02). The effect of alcohol on the incidence of p53 mutations was still statistically significant (RR = 2.24; 95% CI, 1.21-4.15) after adjustment for cigarette smoking and betel quid (BQ) chewing. G:C to A:T transitions were the predominant mutations observed and associated with BQ and tobacco use. Alcohol drinking could enhance these transitions. After adjustment for cigarette smoking and BQ chewing, alcohol drinking still showed an independent effect on G:C to A:T transitions (RR = 2.41; 95% CI, 1.01-5.74). These findings strongly suggest an important contributive role of tobacco carcinogens to p53 mutation in this series of Taiwanese OSCCs and alcohol might enhance these mutagenic effects. As safrole-DNA adducts have been detected in 77% (23/30) of the OSCC tissues from Taiwanese oral cancer patients with a BQ chewing history, we cannot rule out the possibility that safrole or other carcinogens present in the BQ may cause a similar pattern of mutagenesis. Determination of the role of safrole and other carcinogens present in BQ on the pattern of p53 gene mutation in OSCC will require further study.
Carcinogenesis 2001 Sep
PMID:Characteristics of mutations in the p53 gene in oral squamous cell carcinoma associated with betel quid chewing and cigarette smoking in Taiwanese. 1153 72

There are 600 million betel quid (BQ) chewers in the world. BQ chewing is a major etiologic factor of oral cancer. Areca nut (AN) and arecoline may inhibit the growth of oral mucosal fibroblasts (OMF) and keratinocytes. In this study, AN extract (100-800 microg/ml) and arecoline (20-120 microM) inhibited the growth of oral KB cells by 36-90 and 15-75%, respectively. Exposure to arecoline (> 0.2 mM) for 24 h induced G(2)/M cell cycle arrest of OMF and KB cells. Areca nut extract (> 400 microg/ml) also induced G(2)/M arrest of KB cells, being preceded by S-phase arrest at 7-h of exposure. No evident sub-G(0)/G(1) peak was noted. Marked retraction and intracellular vacuoles formation of OMF and KB cells were observed. Glutathione (GSH) level, mitochondrial membrane potential (Deltabetam) and H(2)O(2) production of KB cells were measured by flow cytometry. GSH level [indicated by 5-chloromethyl-fluorescein (CMF) fluorescence] was depleted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 microg/ml), with increasing the percentage of cells in low CMF fluorescence. By contrast, arecoline (0.1-1.2 mM) and AN extract (800-1200 microg/ml) induced decreasing and increasing H(2)O(2) production (by 2',7'-dichloro- fluorescein fluorescence), respectively. Hyperpolarization of Deltabetam (increasing of rhodamine uptake) was noted by 24-h exposure of KB cells to arecoline (0.4-1.2 mM) and AN extract (800-1200 microg/ml). AN extract (100- 1200 microg/ml) and arecoline (0.1-1.2 mM) induced little DNA fragmentation on KB cells within 24 h. These results indicate that AN ingredients are crucial in the pathogenesis of oral submucous fibrosis (OSF) and oral cancer by differentially inducing the dysregulation of cell cycle control, Deltabetam, GSH level and intracellular H(2)O(2) production, these events being not coupled with cellular apoptosis.
Carcinogenesis 2001 Sep
PMID:Areca nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral KB epithelial cells: association of glutathione, reactive oxygen species and mitochondrial membrane potential. 1153 76


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