UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA methylation is an important mechanism for gene silence. The purpose of this study was to investigate aberrant promoter methylation of the p16 and FHIT genes in tissues and plasma and loss of protein expression in esophageal precancerous conditions (EPC) and esophageal squamous cell carcinoma (ESCC) of high-risk area. Methylation-specific PCR(MSP) was employed to examine the DNA methylation in the plasma and tissues of 95 patients of EPC, ESCC and 10 chronic esophagitis (CE). Loss of protein expression of p16 and FHIT was detected immunohistochemically. In total 95 lesion tissues of EPC and ESCC, p16 methylation was found in 53 (55.79%) cases, and 41 of 53 (77.36%) cases were demonstrated deletion of the p16 protein immunohistochemically. FHIT methylation was found in 49 (51.58%) cases, and 40 of 49 (81.63%) were demonstrated deletion of the FHIT protein. Only 1 (10%) case of 10 CE p16 methylation was found in the tissues. In the plasma of total 105 samples, 2 of 23 high grade intraepithelial neoplasia (HGIN) and 12 of 37 ESCC were detected p16 methylation, and 2 of 23 HGIN and 14 of 37 ESCC were detected FHIT methylation. These results indicate that p16 and FHIT methylation may be one of the earliest events and an important mechanism for gene silencing in esophageal squamous cell carcinogenesis. This study may be helpful for screening the candidate molecular markers for early diagnosis of ESCC in high-risk area.
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PMID:DNA methylation and loss of protein expression in esophageal squamous cell carcinogenesis of high-risk area. 1836 57

In cell cycle, most of the regulatory actions occur at the so-called restriction point (R) in the late G1 phase. Tumor suppressor genes; Rb, p53 and p21 are among the most important of the agents suppressing transition through R point. Changes in the expression of Rb (retinoblastoma) gene correlate with the presence of Rb protein and they are believed to be an early event in carcinogenesis. This issue seems to be not plainly defined in laryngeal cancer. P21 with p16, cyclin D1 and Rb genes that play a critical role in the regulation of the G1-S transition of the cell cycle, are frequently altered in several neoplastic entities. Our purpose was to investigate the possible prognostic value of p21, p16 and Rb proteins in patients with laryngeal cancer. 67 patients with laryngeal cancer was multi-variously analysed. Paraffin-embedded tissue sections were immunohistochemically stained with a monoclonal antibody raised against p21, p16 and Rb proteins using standard immunohistochemistry techniques. Low intensity (< or = 10%, 7/67) of p21 protein expression was significantly correlated with histological grading (p < 0,01) and overall and disease free survival (p < 0,05). We did not observed any correlation between p21 expression and T, N and M status and local or nodal recurrences. Absence of p16 protein expression was observed in 35/67 (52,2%) cases and was significantly correlated with N status (p = 0,03) and nodal recurrences (p = < 0,01). By univariate analysis expression of p16 protein was related with quicker relapse. Rb protein was absent in 7/67 cases (10,4%) and was related to T3 and T4 primary tumour size (p < 0,05). We did not observed any correlation between Rb and other clinocopathological features (p > 0,05). Our study has identified p21 protein expression as important biological marker which may indicate the progression of laryngeal squamous cell carcinoma. P16 protein has a prognostic value in assessment of disease free survival. Based on this findings it can be deduced that investigation of Rb, p16 and p21 proteins makes it easier to understand the process of cancerogenesis in laryngeal cancer and to establish its prognostic value further research and observations need to be attempted.
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PMID:[Alterations of cell cycle regulating proteins: Rb, p21 and p16 in laryngeal cancer]. 1854 41

p16(CDKN2A) is one of the most important tumor-suppressor genes and has been investigated widely in recent years for its role in oral carcinogenesis, but few have explored the relationship between its RNA and protein, especially in precancerous tissues. The aim of this study was to explore the relationship of mRNA and protein level of p16(CDKN2A) in rat tongue carcinogenesis process induced by 4-nitroquinoline-1-oxide. By the use of semi-quantitative RT-PCR, immunohistochemistry (IHC) and Western Blot, histologically normal, premalignant and invasive squamous cell carcinoma samples from the animal model were explored respectively. The results showed the levels of mRNA of p16(CDKN2A) did not significantly change during the carcinogenesis process when compared with controls. However, detectable level of P16 protein expression was lost in both the dysplasia and carcinoma groups. We could conclude that p16(CDKN2A) in 4NQO-induced rat tongue carcinogenesis might be inactivated predominantly by posttranscriptional regulation.
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PMID:p16(CDKN2A) expression during rat tongue carcinogenesis induced by 4-nitroquinoline-1-oxide. 1880 14

Endometrial serous carcinomas (ESC) constitute only approximately 10% of endometrial cancers, but have a substantially higher case-fatality rate than their more common endometrioid counterparts. The precise composite of factors driving endometrial serous carcinogenesis and progression remain largely unknown, but we attempt to review the current state of knowledge in this report. ESC probably do not evolve through a single pathway, and their underlying molecular events probably occur early in their evolution. TP53 gene mutations occur in 22.7 to 96% of cases, and p53 protein overexpression is seen in approximately 76%. By gene expression profiling, p16 is upregulated in ESC significantly above both normal endometrial cells and endometrioid carcinomas, and 92-100% of cases display diffuse expression of the p16 protein by immunohistochemistry (IHC). Together, these findings suggest dysregulation of both the p16(INKA)/Cyclin D-CDK/pRb-E2F and the ARF-MDM2-p53 cell cycle pathways in ESC. By IHC, HER2/neu is overexpressed (2+ or 3+) in approximately 32.1% of ESC, and approximately 54.5% of cases scored as 2+ or 3+ by IHC display c-erbB2 gene amplification as assessed by fluorescent in situ hybridization. Genetic instability, typically manifested as loss of heterozygosity in multiple chromosomes, is a common feature of ESC, and one study found loss of heterozygosity at 1p32-33 in 63% of cases. A subset of ESC display protein expression patterns that are characteristic of high grade endometrial carcinomas, including loss of the metastasis suppressor CD82 (KAI-1) and epithelial-to-mesenchymal transformation, the latter manifested as E-cadherin downregulation, P-cadherin upregulation, and expression of epithelial-to-mesenchymal transformation-related molecules such as zinc-finger E-box-binding homeobox 1 (ZEB1) and focal adhesion kinase. Preliminary data suggests differential patterns of expression in ESC of some isoforms of claudins, proteases, the tumor invasiveness and progression-associated oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3), as well as a variety of other molecules. At the morphologic level, evidence that indicates that endometrial glandular dysplasia (EmGD) is the most likely morphologically recognizable precursor lesion to ESC is presented. We advocate use of the term endometrial intraepithelial carcinoma (EIC, or its other appellations) only as a morphologic descriptor and never as a diagnostic/pathologic statement of biologic potential. Given its potential for extrauterine extension, we consider the lesions described as EIC, when present in isolation, as examples of localized ESC, and patients should be managed as such. Morphologically normal, p53 immunoreactive endometrial cells (the so-called "p53 signatures"), show a statistically significant association with ESC, display p53 mutations in a significant subset, and form the start of a progression model, outlined herein, from p53 signatures to EmGD to localized ESC to the more conventionally invasive neoplasm. The identification of a morphologically-recognizable precursor holds the promise of early detection of ESC, with the attendant reduction in its overall associated mortality rate. Deciphering the molecular basis for endometrial serous carcinogenesis should uncover potential targets for diagnosis, therapy, and/or disease surveillance.
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PMID:Insights into endometrial serous carcinogenesis and progression. 1929 1

3-methylcholanthrene (MCA) and diethylnitrosamine (DEN) are typical genotoxic carcinogens that can induce tumors in a variety of human and rodent tissues. However, the epigenetic mechanisms underlying their tumorigenesis are unclear. In this study we used a MCA/DEN-induced multistep lung carcinogenesis rat model to study the evolution of alterations in DNA methylation. Rats were treated with a single dose of MCA and DEN in iodized oil by left intra-bronchial instillation. The animals were killed on days 15, 35, 55, 65 and 75 and samples of various pathological phases during carcinogenesis were obtained on these days. The status of global methylation was analyzed for each sample using a monoclonal antibody specific for 5-methycytosine (5-mC) and quantified by image analysis software. We found that the degree of global methylation was, in general, higher in basal cells compared to luminal cells of normal, precancerous and tumor tissues. The combined 5-mC scores of different types of tissues decreased gradually during the progression of carcinogenesis. We also used methylation-sensitive arbitrarily primed PCR (MS-AP-PCR) to screen a total of eight differentially methylated DNA fragments in both precancerous and tumor tissues isolated using laser capture microdissection (LCM), and observed that both unique hypomethylation and hypermethylation fragments coexist after exposure to genotoxic carcinogens. Remarkably, epigenetic alterations in p16 (CDKN2A), but not in p15 (CDKN2B), were observed, and these correlated with the presence of pathologic lung lesions and loss of p16 protein expression. Moreover, defective expression of p16 in methylated primary tumor cell lines recovered markedly after treated with 5-aza-2'-deoxycytidine (5-aza-dC). These results suggest that DNA methylation alterations are an early event in tumorigenesis and play an important role during MCA/DEN-induced multistep rat lung carcinogenesis.
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PMID:Dynamic changes in DNA methylation during multistep rat lung carcinogenesis induced by 3-methylcholanthrene and diethylnitrosamine. 1940 58

Abnormalities of Rb-pathway components are common in the formation of cancer. The immunostaining for cyclin D1 and p16 protein was applied on 1 mm serial tissue microarray (TMA) paraffin sections. Tissue microarray (TMAs) is potentially a good method to find the molecular features of the genes and expressions of them. The aim of this study was to evaluate the protein expressions of cyclin D1 and p16 genes in squamous cell carcinomas (SCCs) of skin and compare with the normal skin tissue. Twenty-five cases of cutaneous SCCs expressed cyclin D1 and p16 proteins. All SCCs samples on the slides showed positive protein expressions of cyclin D1 and p16 genes. Our findings suggested that the increased protein expressions of cyclin D1 and p16 genes might lead to aberrant expressions of these proteins in the affected tumor cells. This study demonstrated that cell cycle controlled deregulation and uncontrolled cell cycle progression might result in the carcinogenesis.
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PMID:Increased protein expression of p16 and cyclin D1 in squamous cell carcinoma tissues. 2010 31

Previously, we showed that PIK3CA and p53 alterations in uterine endometrial carcinomas correlate with poor prognosis. However, the contribution of phosphatidylinositol 3-kinase (PI3K) -AKT deregulation to endometrial carcinogenesis is not completely understood. The purpose of this study was to analyze alterations of this pathway in endometrial carcinomas and correlate them with the most common genetic abnormalities. Expression profiling of 22 genes involved in PI3K-AKT signaling pathway was analyzed in 38 endometrial carcinomas using TaqMan low-density array (TLDA) analysis. The gene expression pattern was analyzed by hierarchical clustering analysis. Unsupervised clustering divided the high-grade endometrial carcinomas into two clusters. One cluster identified tumors with alterations in the PI3K-AKT signaling pathway (exon 20 PIK3CA mutations and/or PTEN mutations 9/15; 60%), and p16 protein overexpression (8/13; 62%). Almost all non-endometrioid adenocarcinomas (serous and clear cell adenocarcinomas) were segregated into this cluster. In contrast, the other cluster identified tumors with p53 alterations (6/6; 100%), p16 protein overexpression (5/5; 100%), and exon 9 PIK3CA mutations (2/6; 33%). Exon 20 PIK3CA and PTEN mutations were not found in this subgroup. Low-grade endometrial carcinomas clustered in a third subgroup characterized by high frequency of PTEN mutations (10/17; 59%) and microsatellite instability (6/17; 35%). Our results show that gene expression profile differences in the PI3K-AKT signaling pathway identify two subgroups of high-grade endometrial carcinomas with different molecular alterations (PI3K-AKT pathway vs p53 alterations) that may have distinct roles in endometrial carcinogenesis. Identification of these subgroups can provide insight into the biology of these tumors and may facilitate the development of future treatments.
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PMID:Expression profiling of 22 genes involved in the PI3K-AKT pathway identifies two subgroups of high-grade endometrial carcinomas with different molecular alterations. 2017 32

Although the association and clinical significance of human papillomavirus (HPV) infections with a subset of head and neck cancers, particularly for oropharyngeal carcinoma, has recently been well documented, the involvement of HPV in laryngeal cancer has been inadequately evaluated. Herein we review the currently known associations of HPV infections in diseases of the larynx and their potential for oncogenicity. Using several methods of detection, HPV DNA has been detected in benign (papillomatosis), indolent (verrucous carcinoma), and malignant (squamous cell carcinoma) lesions of the larynx. Consistent with the known oncogenic risk of HPV infections, common HPV types associated with laryngeal papillomatosis include low-risk HPV types 6 and 11, with high-risk HPV types 16 and 18 more commonly present in neoplastic lesions (verrucous carcinoma and squamous cell carcinoma). Although a broad range of prevalence has been noted in individual studies, approximately 25% of laryngeal squamous cell carcinomas harbor HPV infections on meta-analysis, with common involvement of high-risk HPV types 16 (highest frequency) and 18. Preliminary results suggest that these high-risk HPV infections seem to be biologically relevant in laryngeal carcinogenesis, manifested as having viral DNA integration in the cancer cell genome and increased expression of the p16 protein. Despite this knowledge, the clinical significance of these infections and the implications on disease prevention and treatment are unclear and require further investigation.
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PMID:Human papillomavirus infections in laryngeal cancer. 2084 41

Carcinogenesis concerns several changes that eventually result in the inactivation of tumor suppressor genes and activation of protooncogenes, leading to loss of cell cycle control. Inactivation of p16 seems to be an early event in this process and occurs in approximately 80% of squamous cell carcinoma cases. The aims of this study were to evaluate the immunohistochemical expression of p16 protein in oral and oropharyngeal squamous cell carcinoma cases, with both the tumoral area itself and its surgical margin being analyzed (dysplastic areas and histologically normal epithelium adjacent to carcinoma), and to verify the presence of human papillomavirus (HPV) and its relation to p16 expression. Paraffin-embedded biopsy tissues from 26 patients, 13 with oral squamous cell carcinoma and 13 with oropharyngeal squamous cell carcinoma, comprised the analyzed samples. To detect HPV, a nested polymerase chain reaction test using PGMY 09/11 and GP5*/GP6* primers and visualization of the product on a 2% agarose gel was performed. Demographic data were obtained from medical records. The results showed low expression of p16 in the tumor area (38.46%), compared with surgical margins in the histologically normal epithelium (84.6%) and dysplastic areas (57.7%). These findings indicate the inactivation of p16 in the process of malignant transformation. The association described in the literature between expression of p16 and presence of HPV could not be verified in this study, because none of the cases was HPV positive.
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PMID:Evaluation of immunohistochemical expression of p16 and presence of human papillomavirus in oral and oropharyngeal carcinoma. 2440 80

Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case-control studies (retrospective) and one nested case-control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low-risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer.
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PMID:No causal association identified for human papillomavirus infections in lung cancer. 2476 Apr 22

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