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)

Toxicology and carcinogenesis studies of pentachloronitrobenzene (99% pure), a fungicide, were conducted by administering diets containing 0, 2,500, or 5,000 ppm pentachloronitrobenzene to groups of 50 B6C3F1 mice of each sex for 103 weeks. These doses were selected because, in 13-week studies in which the chemical was administered in feed at doses up to 20,000 ppm in male mice and up to 40,000 ppm in female mice, body weight gain depression was observed at 10,000 ppm and above in males and female and deaths occurred at 40,000 ppm in females. The National Cancer Institute had conducted 2-year (diet) studies in B6C3F1 mice and Osborne-Mendel rats (See TR-61 reported in 1978). Survival among male mice was low, not all livers were examined from dosed female mice, and the size of the control group was considered to be small. For these reasons, the NCI decided to conduct additional 13-week and 2-year studies in B6C3F1 mice. Under the conditions of the NCI studies, pentachloronitrobenzene was not carcinogenic in either Osborne-Mendel rats or B6C3F1 mice. In the studies reported in this Technical Report, the survival of male mice was comparable among control and dosed groups (control, 35/50; low dose, 31/50; high dose, 32/50). Final mean body weights of low dose and high dose male mice were 96% and 90% that of the controls. All groups of female mice showed evidence of bacterial infection. At week 84, survival in dosed and control female mice was 38/50; 34/50; 30/50; after week 84, survival in dosed groups decreased, with the final survival being 30/50; 20/50; 15/50. The mean body weight of high dose female mice was more than 10% lower than that of the control group after week 20 and was 21% lower than controls at week 104. The mean body weight of low dose female mice was within 10% that of the control group until week 88 and was 18% lower than controls at week 104. No compound-related neoplastic lesions were seen in either male or female mice. The nonneoplastic lesions observed in female mice were considered to be secondary to bacterial infection (primarily Klebsiella) and included hematopoiesis of the liver (9/50; 21/50; 23/50) and spleen (14/50; 23/48; 27/50), plasma cell hyperplasia of the mediastinal lymph nodes (1/44; 4/47; 9/45), and ovarian abscesses (12/49; 22/50; 29/50). Pentachloronitrobenzene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Syrian hamster or male Sprague-Dawley rat liver S9 when tested according to the preincubational protocol. Pentachloronitrobenzene was not mutagenic at the TK+/- locus of L5178Y mouse lymphoma cells in the presence or absence of Aroclor 1254-induced F344/N rat liver S9. In cultured Chinese hamster ovary cells, pentachloronitrobenzene did not induce sister-chromatid exchanges but did induce chromosomal aberrations both with and without Aroclor 1254-induced male Sprague-Dawley rat liver S9. An audit of the experimental data was conducted for the 2-year studies of pentachloronitrobenzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year feed studies, there was no evidence of carcinogenicity for either male or female B6C3F1 mice receiving 2,500 or 5,000 ppm of pentachloronitrobenzene. Infection is considered to have decreased survival of the female mice and thus reduced the sensitivity for determining the presence or absence of a carcinogenic response. Synonyms or Trade Names: Avicolreg.; PCNB; quintozene; Botrilexreg.; Brassicolreg.;Folosanreg.; PKhNB; Tilcarexreg.; Terraclorreg.; Tritosanreg.
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PMID:NTP Toxicology and Carcinogenesis Studies of Pentachloronitrobenzene (CAS No. 82-68-8) in B6C3F1 Mice (Feed Studies). 1274 28

Infection with human papillomaviruses (HPV) is essential in the carcinogenesis of the uterine cervix. However, a complex interrelation between viral and cellular genes is necessary for cell-cycle control deregulation and development and progression of cervical cancer induction. The TP73 gene is localized in 1p36.3 band, which is often deleted by loss of heterozygosity (LOH) in human cancers. We analyzed the p73 cytosine thymine polymorphism and LOH in this locus by polymerase chain reaction restriction fragment length polymorphism in 134 DNA samples from biopsies of 67 primary untreated invasive cervix tumors and the corresponding peripheral blood. Genotype frequencies of 56.7% for homozygous genotype GC/GC and 43.3% for heterozygous genotype GC/AT were found. The presence of the GC/AT genotype in tumors was associated with lower age at menarche (P=0.039) and high parity (P=0.015). In 20.0% of DNA tumor samples, the AT allele was lost compared with their DNA normal blood pairs. The AT allele was conserved in women with high parity. This was not the case in the group with low parity, with 33.3% of patients showing loss of the AT allele in tumor DNA (P=0.041). These results suggest that TP73 genetic alterations may contribute to the genesis and/or progression of cervical carcinoma in an HPV-infected transformation zone under prolonged exposure to events related to pregnancy.
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PMID:TP73 alterations in cervical carcinoma. 1506 18

Despite major progress in the reduction of incidence and mortality of cervical carcinoma through systematic screening by cytology, there are areas which deserve further improvement, one of them being the obvious overtreatment of CIN 3 which has to be removed in all patients although the invasive potential is limited to a minority of those lesions. Based on new knowledge of cervical carcinogenesis uncovered in the last few years, new potential targets for an individualized determination of prognostic behaviour may become possible. Infection by high-risk HPV types has been recognized as an essential step in the development of cervical carcinoma. In virally induced cervical carcinogenesis, dysregulation of the cell cycle is induced by an overexpression of the oncogenes E6 and E7. Direct determination of these oncogenes may become possible by mRNA measurements. Other biomarkers of cell cycle dysregulation such as p16 may serve in the future to determine the invasive potential of the precursors of cervical carcinoma. Further discoveries in molecular carcinogenesis may possibly allow to develop new diagnostic markers and possibly therapeutic agents in the future.
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PMID:[Molecular diagnosis of cervical neoplasia: future potential or academic playground?]. 1521 Oct 61

Infection with strains of Helicobacter pylori that carry the cytotoxin-associated antigen A (cagA) gene is associated with gastric carcinoma. Recent studies have shed light on the mechanism through which the cagA gene product, CagA, elicits pathophysiological actions. CagA is delivered into gastric epithelial cells by the bacterial type IV secretion system, where it deregulates the SHP2 oncoprotein. Intriguingly, CagA is noted for its variation, particularly at the SHP2-binding site, which could affect the potential of different strains of H. pylori to promote gastric carcinogenesis.
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PMID:Oncogenic mechanisms of the Helicobacter pylori CagA protein. 1534 75

Heat shock proteins (HSPs) are crucial for the maintenance of cell integrity during normal cellular growth as well as during pathophysiological conditions. While functioning mainly as molecular chaperones, HSPs also appear to be involved in diverse biological activities, such as apoptosis, carcinogenesis, and cytoprotection from cytotoxic damage. Infection with Helicobacter pylori causes inflammation in the gastric mucosa, leading to gastritis, gastric ulcers, duodenal ulcer disease, and even gastric cancer, but the role of HSPs in H. pylori-associated gastropathy is not known. Using two-dimensional electrophoretic analysis, we have observed significant shifts in HSP profiles after H. pylori infection in RGM-1 cells. We therefore evaluated the effect of treatments that induce HSPs on H. pylori-induced inducible nitric oxide synthase (iNOS) expression. We found that H. pylori infection significantly attenuated the expression of HSP70, whereas exposure of cells to noncytotoxic heat shock or geranylgeranylacetone restored HSP70 expression, as well as suppressing the expression of iNOS, a major cause of H. pylori-induced gastric tissue damage. Our results suggest that induction of HSP70 confers cytoprotection against H. pylori infection by inhibiting the expression of iNOS. In conclusion, these results provide important insights into the flux in HSPs profiles in response to H. pylori infection and highlight the cytoprotective role of HSP70 in H. pylori infection.
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PMID:Restoration of heat shock protein70 suppresses gastric mucosal inducible nitric oxide synthase expression induced by Helicobacter pylori. 1537 40

Infection with human papillomaviruses is strongly associated with the development of multiple cancers including esophageal squamous cell carcinoma. The HPV E6 gene is essential for the oncogenic potential of HPV. The regulation of apoptosis by oncogene has been related to carcinogenesis closely; therefore, the modulation of E6 on cellular apoptosis has become a hot research topic recently. Inactivation of the pro-apoptotic tumor suppressor p53 by E6 is an important mechanism by which E6 promotes cell growth; it is expected that inactivation of p53 by E6 should lead to a reduction in cellular apoptosis, numerous studies showed that E6 could in fact sensitize cells to apoptosis. The molecular basis for apoptosis modulation by E6 is poorly understood. In this article, we will present an overview of observations and current understanding of molecular basis for E6-induced apoptosis.
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PMID:Regulation of apoptosis by the papillomavirus E6 oncogene. 1574 91

Infection with high-risk human papillomavirus (HR-HPV) has been associated with intraepithelial neoplasia and carcinomas at various sites of the anogenital tract, including the cervix, vulva, vagina, penis and anus. Although HR-HPV is a necessary cause for cervical cancer, the majority of anal cancers and a subset of cancers at other genital sites, additional (epi)genetic events are required for malignant transformation. HPV-mediated transformation of human epithelial cells has been recognized as a multi-step process resulting from deregulated transcription of the viral oncogenes E6 and E7 in the proliferating cells. Interference of E6 and E7 with cell cycle regulators induces genetic instability, which drives the continuous selection of oncogenic alterations providing cells with a malignant phenotype. Early genetic events during cervical carcinogenesis associated with immortalization, include deletions at chromosomes 3p, 6 and 10p, whereas amongst others gain of chromosome 3q, loss of chromosome 11 and epigenetic alterations such as inactivation of the TSLC1 tumor suppressor gene represent later events associated with tumor invasion.
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PMID:HPV-mediated transformation of the anogenital tract. 1575 9

Infection with oncogenic human papillomaviruses (HPVs), typified by HPV type 16 (HPV16), is a necessary cause of cervical cancer. Prophylactic vaccination with HPV16 L1 virus-like particles (VLPs) provides immunity. HPV16 VLPs activate dendritic cells and a potent neutralizing immunoglobulin G (IgG) response, yet many cervical cancer patients fail to generate detectable VLP-specific IgG. Therefore, we examined the role of the innate recognition of HPV16 L1 in VLP-induced immune responses and its evasion during carcinogenesis. Nonconservative mutations within HPV16 L1 have been described in isolates from cervical cancer and its precursor, high-grade cervical intraepithelial neoplasia (CIN). We determined the effect of mutations in L1 upon in vitro self-assembly into VLPs and their influence upon the induction of innate and adaptive immune responses in mice. Several nonconservative mutations in HPV16 L1 isolated from high-grade CIN or cervical carcinoma prevent self-assembly of L1 VLPs. Intact VLPs, but not assembly-defective L1, activate dendritic cells to produce proinflammatory factors, such as alpha interferon, that play a critical role in inducing adaptive immunity. Indeed, effective induction of L1-specific IgG1 and IgG2a was dependent upon intact VLP structure. Dendritic cell activation and production of virus-specific neutralizing IgG by VLPs requires MyD88-dependent signaling, although the L1 structure that initiates MyD88-mediated signaling is distinct from the neutralizing epitopes. We conclude that innate recognition of the intact L1 VLP structure via MyD88 is critical in the induction of high-titer neutralizing IgG. Tumor progression is associated with genetic instability and L1 mutants. Selection for assembly-deficient L1 mutations suggests the evasion of MyD88-dependent immune control during cervical carcinogenesis.
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PMID:Papillomavirus capsid mutation to escape dendritic cell-dependent innate immunity in cervical cancer. 1589 Sep 12

The aetiology of squamous cell carcinomas of the head and neck (HNSCC) is multifactorial. Oncogenic human papillomaviruses (HPVs), a causative agent in uterine cervical cancer, have also been repeatedly detected in HNSCC, especially in squamous cell carcinomas of tonsils. Approximately half the HPV DNA-positive HNSCC contain detectable E6/E7 transcripts with wild-type p53, reduced pRb and overexpressed p16 in the tumours. HPV-16 is the predominant type and exists in episomal, integrated, or mixed forms. Tonsillar carcinomas have a remarkably higher viral load than carcinomas at other sites of the head and neck region. HPV-16 DNA has also been detected in tumour-free tonsils. Infection by oncogenic HPVs is a necessary but not a sufficient cause of cancers. Studies on the molecular mechanisms underlying HPV-associated carcinogenesis are difficult, because HPV is not easy to propagate in vitro. HPV-immortalised human tonsillar epithelial cell lines may provide an in vitro model to study co-factors for the HPV-associated tonsillar cancers and to test the effects of anti-viral and anti-tumour agents.
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PMID:Human papillomavirus type 16 in head and neck carcinogenesis. 1594 78

Infection with the hepatitis B virus has been identified as one of the major causes of liver cancer. A large body of experimental work points to a central role for the virally encoded protein HBx in this form of carcinogenesis. HBx is expressed in HBV-infected liver cells and interacts with a wide range of cellular proteins, thereby interfering in cellular processes including cell signaling, cycle regulation and apoptosis. In order to identify possible new targets of the HBx protein, we performed a yeast two-hybrid screen using a truncated protein mini-HBx(18-142) as the bait. In addition to known interacting partners, such as RXR and UVDDB1, we identified several new candidates including the human transcriptional regulatory protein p120E4F, which has been implicated in the regulation of mitosis and the cell cycle. In vitro pull down experiments confirmed the interaction and transcription activation assays in the yeast demonstrated that HBx protein was able to repress GAL4AD-p120E4F-dependent activation of a reporter gene under the control of E4F binding sites found in the adenovirus E4 promoter and the HBV enhancer II region. We also showed that the cysteine residues in HBx are necessary for its interaction with UVDDB1 but not for the interaction with RXR or p120E4F. The possible functional relevance of the interaction between HBx and E4F proteins is discussed in the contexts of cellular transformation and host-virus co-evolution.
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PMID:Interaction of the hepatitis B virus protein HBx with the human transcription regulatory protein p120E4F in vitro. 1611 66


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