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)

The purpose of this study was to evaluate whether mandatory fortification of grain products with folic acid in the USA is associated with changes in global DNA methylation in cells involved in cervical carcinogenesis. Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before (1990-92) and after mandatory folic acid fortification (2000-02) were used to examine for global DNA methylation in specific lesions involved in cervical carcinogenesis by using a monoclonal antibody specific for 5 methyl cytosine (5-mc). The total number of lesions examined was 152 in the pre-fortification period and 172 in the post-fortification period. Immunohistochemical staining for 5-mc, the assessment of methylation status and data entry were blinded with regard to the fortification status. Age- and race-adjusted mean percentage of cells positive for 5-mc or the 5-mc score was not significantly different (P>0.05) between the pre- and post fortification periods in any of the individual lesions evaluated (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN or carcinoma in situ). The degree of global DNA methylation was significantly higher (P<0.0001) in >or= CIN 2 lesions compared to <or= CIN 1 lesions, regardless of the fortification group. These results suggest that mandatory fortification with folic acid in the United States has not resulted in a change in the degree or the pattern of global DNA methylation in cells involved in cervical carcinogenesis.
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PMID:Mandatory fortification with folic acid in the United States is not associated with changes in the degree or the pattern of global DNA methylation in cells involved in cervical carcinogenesis. 1726 97

Human telomerase reverse transcriptase (hTERT) and human nonmetastatic clone 23 (nm23-H1) may be separately involved in tumor progression of uterine cervix. We therefore investigate the correlations of hTERT and nm23-H1 in cervical carcinogenesis and further check their application. One hundred and twenty-eight cervical tissues, including 48 squamous cell carcinoma (SCC), 36 high-grade cervical intraepithelial neoplasia (CIN) (CIN 2 and CIN 3), 20 low-grade CIN 1, and 24 normal cases, were collected for immunohistochemical expression of hTERT and nm23-H1. Spearman rank correlation analysis was applied to assess their correlation in these samples. The Fisher exact or Chi-square test was used to evaluate the expression of hTERT or nm23-H1 among each subgroup. The sensitivity, specificity, positive and negative predictive values (PPV and NPV), and accuracy of hTERT and/or nm23-H1 were calculated for the prediction of high-grade CIN and SCC. We found normal cervix and CIN 1 samples had concurrent low expression of hTERT and nm23-H1, whereas high-grade CIN and SCC samples had concurrent high immunoreactivities. The hTERT alone and hTERT or nm23-H1 in combination had better sensitivity, NPV, and accuracy. The nm23-H1 alone as well as hTERT and nm23-H1 in combination had better specificity and PPV. Our results reveal a significantly positive relationship between expression of hTERT and nm23-H1 in normal and neoplastic tissues of uterine cervix. We suggest high expression of hTERT alone and hTERT or nm23-H1 in combination can be offered additional molecular information correlated with high-grade CIN and SCC.
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PMID:Concurrent high expression of human telomerase reverse transcriptase and human nonmetastatic clone 23 in high-grade squamous intraepithelial neoplasia and squamous cell carcinoma of uterine cervix. 1735 90

Hairy and Enhancer-of-split homologues 1 and 5 (Hes1 and Hes5) are the basic helix-loop-helix transcriptional factors that negatively regulate the cell differentiation during embryogenesis. It has been reported that they may be involved in carcinogenesis in some tumors. The roles of Hes1 and Hes5 in development and progression of cervical carcinoma are not well documented todate. In the study, the expression of Hes1 and Hes5 were detected by immunohistochemistry in 295 cases with various degrees of cervical epithelial lesions, including 78 normal cervical epithelia, 31 mild dysplasia (CIN I), 77 moderate-severe dysplasia (CIN II-III), and 109 squamous cervical carcinomas (SCCs), and their association with various clinical pathologic prognostic variables were analyzed in 73 early-stage SCC patients who underwent surgery. Hes1 and Hes5 expression were found to be significantly higher in SCC compared with CIN as well as higher in CIN than normal cervical epithelia, and positively correlated with various prognostic factors in early-stage cervical carcinoma. Our findings suggest that Hes1 and Hes5 may be involved in carcinogenesis of the cervix and progression of cervical carcinoma. Hes1 and Hes5 overexpression are probably variables to predict poor prognosis of the patients with early-stage cervical carcinoma.
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PMID:Expression of differentiation associated protein Hes1 and Hes5 in cervical squamous carcinoma and its precursors. 1738 15

Senescence and apoptosis are two key mechanisms that protect against cancer development. Many cell cycle regulators, such as p14(ARF), p15(INK4b) and p16(INK4a), are important in G1 cell cycle arrest and oncogene-induced senescence. The bcl-2 protein is one of the key components that control apoptosis, while the p53 protein plays key roles in both mechanisms. The genes of these key regulator proteins are often mutated or deleted in various malignancies. It is unknown how senescence and apoptosis are regulated in one of the most common tumors of the female genital tract, cervical squamous cell carcinoma (SCC). In this study the, expression of senescence, apoptosis and proliferation markers in normal cervical epithelium, cervical intraepithelial neoplasia (CIN) and SCC are characterized via immunohistochemical staining for p14(ARF), p15(INK4b), p16(INK4a), bcl-2, p53 and Ki-67 in tissue microarray blocks containing 20 samples each of normal cervix, moderate-to-severe cervical dysplasia (CIN II-III) and invasive SCC. Samples are derived from 60 total cases of cervical biopsies and cervical conizations. Results showed that the proliferation marker, Ki-67, is markedly increased, and the senescence markers, p15(INK4b), p16(INK4a) and p14(ARF) are overexpressed in both dysplasia and carcinoma. P53 immunostain is negative in all normal cervical tissue, and positive in dysplasia and carcinoma. Although the expression of bcl-2 is increased in dysplasia, this marker is negative in approximately half of SCC cases. These results suggest that some senescence pathways are activated and are still maintained in cervical dysplasia and carcinoma. However proliferation is increased and carcinogenesis is not thwarted, leading to eventual development of cervical cancer. Other mechanisms, such as those that account for the apparent overexpression of p53 and paradoxical loss of bcl-2 expression in some SCC cases, as well as additional senescence and apoptotic pathways, may play key roles carcinogenesis of cervical SCC.
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PMID:Senescence and apoptosis in carcinogenesis of cervical squamous carcinoma. 1763 54

This study is the first comprehensive, integrated approach to examine grade-specific changes in gene expression along the entire neoplastic spectrum of cervical intraepithelial neoplasia (CIN) in the process of cervical carcinogenesis. This was accomplished by identifying gene expression signatures of disease progression using cDNA microarrays to analyze RNA from laser-captured microdissected epithelium and underlying stroma from normal cervix, graded CINs, cancer, and patient-matched normal cervical tissues. A separate set of samples were subsequently validated using a linear mixed model that is ideal to control for interpatient gene expression profile variation, such as age and race. These validated genes were ultimately used to propose a genomically based model of the early events in cervical neoplastic transformation. In this model, the CIN 1 transition coincides with a proproliferative/immunosuppression gene signature in the epithelium that probably represents the epithelial response to human papillomavirus infection. The CIN 2 transition coincides with a proangiogenic signature, suggesting a cooperative signaling interaction between stroma and tumor cells. Finally, the CIN 3 and squamous cell carcinoma antigen transition coincide with a proinvasive gene signature that may be a response to epithelial tumor cell overcrowding. This work strongly suggests that premalignant cells experience a series of microenvironmental stresses at the epithelium/stroma cell interface that must be overcome to progress into a transformed phenotype and identifies the order of these events in vivo and their association with specific CIN transitions.
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PMID:Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates. 1767 Nov 78

The cell cycle control system includes cyclins, cyclin-dependent kinases (CDK), and their inhibitors (CDK1). Extracellular regulated kinase (ERK1/2) (p44 and p42 mitogen-activated protein kinases [MAPKs]) is a component of the MAPK pathway, which is associated with cyclin D1 and CDK. It is a critical signaling system for the induction of cell proliferation, differentiation, and cell survival. The aim of this study was to investigate the usefulness of ERK2 expression as a marker of biological aggressiveness complementary to cervical intraepithelial neoplasia (CIN) grade as well as to compare its expression in preinvasive lesions with that in invasive carcinoma. Paraffin-embedded sections of 146 CIN lesions (32 CIN I, 49 CIN II, and 43 CIN III) and 22 invasive cervical carcinomas (13 squamous and 9 adenocarcinomas) were used for the standard immunohistochemical procedure with the application of the ERK2 monoclonal antibody. ERK2 staining displayed a cytoplasmic and nuclear pattern. The staining intensity was gradually increased according to the severity of the dysplastic lesions; ERK2 immunoreactivity was significantly increased in high-grade dysplastic lesions (CIN II and CIN III) and invasive carcinomas by comparison to low-grade dysplastic lesions (CIN I) (P < 0.001). When high-grade lesions were separately assessed, the differences between each one of them and CIN I retained their statistical significance: CIN II versus CIN I (P < 0.001) and CIN III versus CIN I (P < 0.001). In conclusion, our study found a direct relationship between the increasing grade of the dysplastic cervical lesions and the intensity of ERK2 staining, thus implying a role of ERK2 as an early event in cervical carcinogenesis.
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PMID:Extracellular regulated kinase-2 immunoreactivity increases in parallel with cervical intraepithelial neoplasia grade in cervical neoplasia. 1796 Nov 62

Infection load and the integration of human papillomaviruses (HPV) have been implicated as determinants for oncogenesis, but whether variation among different HPV types exists remains unclear. We investigated 91 women infected with HPV type 52 (HPV-52), a type that is rare worldwide but common in East Asia. The median viral load increased with the severity of the lesion (248 copies/cell equivalent for normal/cervical intraepithelial neoplasia [CIN] grade 1, 402 copies/cell equivalent for CIN 2, 523 copies/cell equivalent for CIN 3, and 1,435 copies/cell equivalent for invasive cancer). The proportion of specimens with integration increased significantly with the severity of the lesion (P < 0.001). The viral load was associated with the physical status of the viral genome, with higher levels for the pure episomal form (P = 0.001). Infection status should be considered when interpreting viral load data for HPV-52, as single infections with this HPV type were found to have marginally higher viral loads than coinfections (P = 0.051). All except one sample had E2 disruption restricted to only a part of the gene. Integration is a critical step in HPV-52-induced carcinogenesis. The profile of E2 disruption was different from that described for HPV-16, with the amino-terminal region being most frequently involved. Selecting the appropriate E2 region for amplification is critical in studying the integration of HPV-52. In summary, the HPV-52 viral load and the integrated proportion increased with the severity of the cervical lesions but had a different pattern than that of HPV-16.
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PMID:Increase of integration events and infection loads of human papillomavirus type 52 with lesion severity from low-grade cervical lesion to invasive cancer. 1827 18

Altered angiogenesis is an important phenotype of high-grade cervical lesions and invasive cervical carcinomas. Many researchers, including us, have shown that oncoproteins of human papillomavirus could enhance the vascular endothelial growth factor (VEGF) expression. We investigated the change in VEGF and hypoxia-inducible factor-1alpha (HIF-1alpha) expression patterns that occur during the carcinogenesis and progression of cervical cancer. Expressions of HIF-1alpha and VEGF were evaluated by immunohistochemistry using paraffin-embedded specimens obtained from 41 patients with a normal cervix, 39 patients with cervical intraepithelial neoplasia (CIN 1, 10; CIN 2/3, 29), and 36 patients with cervical cancer. The VEGF and HIF-1alpha expressions were higher in CIN and invasive cancer than in normal cervix (P= 0.021, P < 0.001, respectively). It is interesting to note that there was no significant difference in VEGF and HIF-1alpha overexpressions between CIN 2/3 and cervical cancer and between nonmetastatic and metastatic cancers. In addition, there was a significant correlation between the immunohistochemical score of HIF-1alpha and that of VEGF expression (Spearman's correlation coefficient 0.275, P= 0.003, n= 116). Taken together, the results of our study suggest that expressions of VEGF and HIF-1alpha could be involved in cervical carcinogenesis. In addition, the weak correlation between VEGF and HIF-1alpha expressions suggests that regulatory mechanisms other than HIF-1alpha may be involved in the expression of VEGF during cervical carcinogenesis.
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PMID:Expression of vascular endothelial growth factor and hypoxia inducible factor-1alpha in cervical neoplasia. 1972 43

We evaluated the relationship between the dietary intake of vegetables and fruits, and the risk of cervical intraepithelial neoplasia (CIN) and determined whether these associations were modified by human papillomavirus (HPV) viral load. We enrolled 1,096 women aged 18-65 to participate in a HPV cohort study from March 2006 up to present. For this analysis, we included 328 HPV-positive women (166 controls, 90 CIN I and 72 CIN II/III). The multivariate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated by multinomial logistic methods. After controlling for potential confounders, we found that a higher HPV viral load was associated with an increased risk of CIN I (OR = 2.68, 95% CI, 1.19-6.04) and CIN II/III (OR = 2.78, 95% CI, 1.15-6.72). The relationships between HPV infection, dietary intake of vegetables and fruits and risk of CIN were not statistically significant. However, subjects with lower intake of vegetables and fruits, and a higher viral load (> or =15.5) have a higher risk of CIN II/III (OR = 2.84(1.26-6.42), interaction p = 0.06 for vegetables; OR = 2.93(1.25-6.87), interaction p = 0.01 for fruits), compared with subjects with lower intake of vegetables and fruits, and a lower viral load (<15.5). Our findings suggest that the dietary intake of vegetables and fruits is associated with the progression of cervical carcinogenesis.
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PMID:The association between fruit and vegetable consumption and HPV viral load in high-risk HPV-positive women with cervical intraepithelial neoplasia. 1977 58

To investigate the significance of PRL-3 expression in progression and metastasis of squamous cell carcinoma of the cervix (SCC). PRL-3 expression was detected by immunohistochemistry in 22 normal cervical epithelia, 30 moderate-severe dysplasia (CIN II-III) and 90 SCC cases. A total of 28 patients with SCC had lymph node metastasis, and PRL-3 expression of metastatic lymph node was detected. The association between PRL-3 expression and various clinical pathological variables in 90 patients with SCC was analyzed. Expression of PRL-3 in SCC was higher than that in normal and CINII-III, as well as higher in CINII-III than in normal (P<0.05 in all instances). PRL-3 expression was significantly different between different tumor sizes, lymph-vascular space invasion status and lymph node metastasis status (P<0.05 in all instances). PRL-3 expression in lymph node metastasis was significantly higher than that in primary SCC (P=0.049). In lymph node metastasis, the frequency of staining in cytoplasm predominantly was higher than that in matched primary cancers (P=0.001). PRL-3 may be involved in carcinogenesis of cervix and lymph node metastases of SCC and serves as an unfavorable prognostic factor in patients with SCC. PRL-3 localization in plasma may be related with cancer progress and metastasis.
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PMID:Expression of phosphatase of regenerating liver-3 in squamous cell carcinoma of the cervix. 2036 35


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