Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the role of p53/p16(INK4a)/RB1 pathways in prostate carcinogenesis, we analyzed the p14(ARF), p16(INK4a), RB1, p21(Waf1), p27(Kip1), PTEN, p73, p53, and MDM2 gene status of multiple areas within 16 histologically heterogeneous prostate carcinomas using methylation-specific polymerase chain reaction, differential polymerase chain reaction, and immunohistochemistry. All focal areas examined had Gleason scores ranging from 1 to 5. Methylation of either PTEN or p73 was undetected in any sample, whereas expression of MDM2 seemed to be an independent event within small foci of 4 of 16 tumors. Loss of p14(ARF), p16(INK4a), RB1, and p27(Kip1) expression correlated with homozygous deletion or promoter hypermethylation. One carcinoma showed co-deletion of both p14(ARF) and p16(INK4a) in two of five areas examined; two areas within another tumor demonstrated concurrent hypermethylation of the promoter regions of the same genes. Focal hypermethylation of RB1, p21(Waf1), and p27(Kip1) was detected within two, two, and three tumors, respectively. These findings indicate that both genetic and epigenetic events occur independently in intratumor foci and further suggest hypermethylation-induced loss of gene function may be as critical as specific genetic mutations in prostate carcinogenesis.
 ...
PMID:Heterogeneous methylation and deletion patterns of the INK4a/ARF locus within prostate carcinomas. 1194 5

We determined inactivation of the CDKN2A (p16(INK4a) and p14(ARF)) gene in 21 cases of oesophageal squamous cell carcinoma (OSCC). The tumours were also analysed for mutations in exons 5-8 and allelic losses in the p53 gene. In addition, we screened the CDKN2B (p15 INK4b), CDKN2C (p18 INK4c), CDK4 and p53R2 genes for mutations in the tumour tissues. Besides concomitant alterations in the CDKN2A and p53 loci in more than half of the cases, our results showed that in 18 OSCC (86%) the CDKN2A (p16(INK4a) and p14(ARF) ) gene was affected through mutations, homozygous/hemizygous deletions and promoter hypermethylation. Eight out of 10 tumours with mutations or promoter hypermethylation specific to the CDKN2A/p16 INK4a gene showed loss of the wild-type allele. One tumour with a single base deletion in the N-terminus (codon 8) of the CDKN2A/p16(INK4a) gene carried a novel germ-line mutation or a rare polymorphism (Ile51Met) in exon 2 of the CDK4 gene. Promoter hypermethylation in the CDKN2A/p14 ARF gene was detected in 11 tumours. In the p53 gene 15 mutations were detected in 14 tumours. We detected an inverse relationship between CDKN2A/p16 INK4a inactivation and frequency of loss of heterozygosity at the p53 locus (OR 0.09, 95% CI 0.01-0.98; Fisher exact test, P-value approximately 0.03). Screening of nine exons of the p53R2 [Human Genome Organisation (HUGO) official name RRM2B] gene resulted in identification of a novel polymorphism in the 5' untranslated region, which was detected in four cases. Our results suggest that the CDKN2A (p16(INK4a) and p14(ARF) ) and p53 genes involved in the two cell cycle pathways are major and independent targets of inactivation in OSCC.
Carcinogenesis 2002 Apr
PMID:Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16(INK4a) and p14(ARF) ) and p53 genes are major targets for inactivation. 1196 Sep 18

The p16(INK4A-ARF) locus plays a crucial role in the control of cellular proliferation via both the Rb and P53 pathways. We previously demonstrated that this locus is altered in human skin carcinomas. In the present study we have studied the expression of the p16(INK4A-ARF) locus following UVB irradiation of normal human keratinocytes both at the mRNA (RT-PCR) and at the protein (Western blotting) levels. Our data confirmed that P16(INK4A) protein is induced by UVB at low (30 mJ cm(2)) and high (100 mJ cm(2)) doses and is observed after a single or repeated exposure implying that this response is involved in both the immediate and adaptative response to UVB. The apparent absence of induction p16(INK4A) mRNA suggested that P16(INK4A) protein is upregulated at the post-transcriptional level. Analysis by flow cytometry and BrdU staining indicated that the highest protein level of P16(INK4A) in the cells was associated with a G(2) cell cycle arrest. Comparative analysis of P16(INK4A) and P53 showed that they were differentially modulated in keratinocytes according to the UVB dose and regimen. Low, acute or repeated UVB exposures led to accumulation of both P16(INK4A) and p53, whereas at high UVB doses, P53 and P53-dependent genes were not induced or even downregulated and only a slight but reproducible stabilization of P16(INK4A) protein was observed. In our conditions, P14(ARF) did not seem to participate in the UV response in these cells as P14(ARF) protein did not vary. These results infer that P16(INK4A) plays a role in cell cycle regulation of keratinocytes submitted to UVB irradiation. They also reinforce our previous demonstration of the importance of inactivation of this gene in UV-induced skin carcinogenesis.
 ...
PMID:P16(INK4A) is implicated in both the immediate and adaptative response of human keratinocytes to UVB irradiation. 1196 38

Pathways involving p53 and pRb tumor suppressor genes are frequently deregulated during lung carcinogenesis. Through its location at the interface of these pathways, Mdm2 can modulate the function of both p53 and pRb genes. We have examined here the pattern of expression of Mdm2 in a series of 192 human lung carcinomas of all histological types using both immunohistochemical and Western blot analyses and four distinct antibodies mapping different epitopes onto the Mdm2 protein. Using Immunohistochemistry (IHC), Mdm2 was overexpressed as compared to normal lung in 31% (60 out of 192) of all tumors analysed, whatever their histological types. Western blotting was performed on 28 out of the 192 tumoral samples. Overexpression of p85/90, p74/76 and p57 Mdm2 isoforms was detected in 18% (5 out of 28), 25% (7 out of 28) and 39% (11 out of 28) of the cases respectively. Overall, overexpression of at least one isoform was observed in 14 out of 28 (50%) lung tumors and concomittant overexpression of at least two isoforms in 7 out of 28 (25%) cases. A good concordance (82%) was observed between immunohistochemical and Western blot data. Interestingly, a highly significant inverse relationship was detected between p14(ARF) loss and Mdm2 overexpression either in NSCLC (P=0.0089) or in NE lung tumors (P<0.0001). Furthermore, a Mdm2/p14(ARF) >1 ratio was correlated with a high grade phenotype among NE tumors overexpressing Mdm2 (P=0.0021). Taken together, these data strongly suggest that p14(ARF)and Mdm2 act on common pathway(s) to regulate p53 and/or pRb-dependent or independent functions and that the Mdm2 : p14(ARF) ratio might act as a rheostat in modulating the activity of both proteins.
 ...
PMID:Mdm2 overexpression and p14(ARF) inactivation are two mutually exclusive events in primary human lung tumors. 1196 48

The INK4 locus has two promoters and encodes two unique proteins that share exons in different reading frames, p16(INK4a) and p14(ARF). The p16(INK4a) protein, by inhibiting cyclin-dependent kinase, down regulates Rb-E2F and leads to cell cycle arrest in the G1 phase. The p14(ARF) protein interacts with the MDM2 protein, neutralizing MDM2-mediated degradation of p53. Since p53/Rb genes are not altered in malignant mesothelioma, additional components of these pathways, such as p16(INK4a) and p14(ARF), are candidates for inactivation. In this study, we have examined p16(INK4a) and p14(ARF) alterations (gene deletion, mutation and promoter methylation) in 45 primary malignant mesothelioma specimens. Fourteen patients (31%) had altered p16; four tumors had a methylated promoter region (8.8%), 10 tumors showed p16 to be deleted (22.2%), and one tumor had a point mutation (2%). We did not find any instances of methylation in the p14(ARF) 5'-CpG island. Patients whose tumors had p16 deletion were significantly younger than those with methylation, and, in the patients whose lungs were studied for the prevalence of asbestos fibers, those with any p16 alteration had lower fiber counts than those with no p16 alteration. Hence, p16 gene alteration is relatively common in malignant mesothelioma, while p14(ARF) is rarely, if ever, methylated. Our data suggest that deletion of p16 occurs in a relatively susceptible subset of the population.
Carcinogenesis 2002 Jul
PMID:Alterations of the p16(INK4) locus in human malignant mesothelial tumors. 1211 69

One of the main regulatory pathways reported to be altered in hepatocellular carcinoma (HCC) is that of cell cycle control involving RB1 gene-related cell inhibitors. We investigated p14(ARF), p15(INK4B), p16(INK4A), p18(INK4C), and RB1 genes in a series of HCCs and associated cirrhosis with the goal of ascertaining their pattern of inactivation by gene methylation. Thirty-three HCCs, adjacent nonneoplastic cirrhotic tissues, and 6 HCC cell lines were studied. Cirrhoses (25 of 33, 76%), HCCs (31 of 33, 94%), and 3 of 6 (50%) cell lines showed 1 or more methylated genes. Cirrhoses (17 of 33, 51%) had more frequently than HCCs (11 of 33, 33%, P =.01) only 1 methylated gene. With the exception of p18(INK4C) the genes under study showed promoter methylation with frequency ranging from 82% (p16(INK4A) in HCC) to 33% and 39% (p15(INK4B) and p16(INK4A) in cirrhoses). In cases with only 1 methylated gene, p15(INK4B) in cirrhosis (8 of 17, 47%) and p16(INK4A) in HCC (10 of 11, 91%) were the more frequently altered. An optimal correlation was found between p15 and p16 gene methylation and complete protein loss in HCC detected by immunocytochemistry, whereas a partial loss of the same proteins was a feature of methylated cirrhoses. Inactivation by DNA methylation of several genes of the RB1 pathway is common to cirrhosis and HCC. An early pattern of methylatory events (1 methylated gene) is a feature of cirrhosis rather than HCC, whereas an advanced one (> or = 3 methylated genes) is characteristic of malignancy. Early methylation changes seem to involve p15(INK4B) and p16(INK4A) in cirrhosis and p16(INK4A) in HCC. In conclusion, a stepwise progression of methylating events is a feature of the sequence cirrhosis-HCC and contributes to the process of hepatic carcinogenesis with potential clinical implications.
 ...
PMID:Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma. 1214 52

Multiple genetic mutations and epigenetic methylation are believed to be involved in prostate carcinogenesis, but it is not known whether these events are independent or correlated in some fashion. We therefore studied 32 prostate adenocarcinomas not only for deletions and / or mutations of multiple suspect genes, but also for aberrant DNA methylation using methylation-specific PCR (MSP). Of those genes examined, p16(INK4a), O(6)-MGMT, and GST-P were found to be the most frequently methylated (66%, 25% and 75% of cases, respectively), while methylations of p14(ARF), RB1, p21(Waf1), and p27(Kip1) were far less common (3%, 6%, 6% and 6% of cases, respectively). Methylation of O(6)-MGMT and GST-P genes was defective in about 19% of the cases and there were occasional simultaneous deletions and methylations of p14(ARF) and p16(INK4a) genes (13% and 3% of cases, respectively). In p16(INK4a), methylation occurred in the promoter region in 9% of samples and in exon 2 in 66% of tumors. Hypermethylation of O(6)-MGMT with concurrent p53 and ras gene mutations were found in 6% and 13% of specimens, respectively; among those tumors with high Gleason scores were 2 carcinomas showing hypermethylated O(6)-MGMT with G-to-A transitions in K-ras. Our results demonstrate that multiple genes of a subset common in prostate carcinomas are methylated and not infrequently show concurrent deletions. Further, there is a suggestion that specific combinations of hypermethylation and mutation correlate to tumor malignancy.
 ...
PMID:DNA hypermethylation status of multiple genes in prostate adenocarcinomas. 1214 42

Abnormal hypermethylation of CpG islands associated with tumor suppressor genes can lead to repression of gene expression and contribute significantly to tumorigenesis. Esophageal squamous cell carcinoma (ESCC) is thought to be developed through a multi-stage process, which involves basal cell hyperplasia (BCH), dysplasia (DYS), carcinoma in situ (CIS) and carcinoma. In the present study, we studied the hypermethylation of 10 selected genes in biopsies from normal individuals and resected tissues from ESCC patients. Tumor and neighboring normal and precancerous tissues including BCH, DYS and CIS were microdissected from the resected tissues by laser capture microdissection. Hypermethylation of CpG islands was examined in these samples for 10 genes: p16(INK4a), p15(INK4b), p14(ARF), human leukocyte antigen (HLA)-A, -B, -C, hMLH1, E-cadherin (E-cad), fragile histidine triad and von Hippel-Lindau (VHL). Methylation of two Alu sequences, which neighbor E-cad and VHL, respectively, was used as control to verify the procedure of DNA extraction and chemical modification. In 48 biopsy samples with BCH or DYS, the most frequent hypermethylated genes were p16(INK4a) (18.8%) and p14(ARF) (14.6%). Seventeen out of these 48 samples (35.4%) contained hypermethylation of at least one gene. In the resected tissues, 52% of the BCH and 81% of the tumors showed hypermethylation of at least one gene. Genes hypermethylated in earlier stage lesions were always found hypermethylated at the later stage lesions in the same patient. All of the genes were methylated at some stages and they were clustered into four groups according to their frequencies. The first group of genes, which consisted of p16(INK4a) and p14(ARF), was most frequently hypermethylated in all stages, and the frequencies increased from normal epithelial (0%) to BCH, to displasia/carcinoma in situ and ESCC. Other genes were hypermethylated less frequently. Our results suggest that hypermethylation of key genes, such as p16(INK4a), p14(ARF) and hMLH1, may be used in combination with other molecular changes, such as p53 mutation, in the development of biomarkers for predicting the risk for ESCC.
Carcinogenesis 2002 Oct
PMID:Detection of multiple gene hypermethylation in the development of esophageal squamous cell carcinoma. 1237 81

Repression of telomerase in the somatic tissues of humans, and probably other long-lived mammals, appears to have evolved as a powerful protective barrier against cancer. Immortalization in vitro of normal human cells that lack telomerase involves the reactivation of telomerase or, rarely, an alternative (ALT) mechanism for maintaining telomeres. Inactivation of the effectors of replicative senescence, i.e. genes encoding one or more elements of the p16/pRB and/or ARF/p53/p21 anti-proliferative pathways, is required for telomerase depression leading to immortalization. Regulation of telomerase in normal human cells is mediated primarily by transcriptional repression of hTERT, the gene encoding the catalytic subunit of telomerase. Rodent cells do not possess stringent controls on telomerase activity in the soma and this explains why they are so readily immortalized and transformed in culture compared with their human counterparts. Because active telomerase has been found to exist in the proliferative compartments of self-renewing tissues, it is not yet clear whether the telomerase present in 90% of human cancers exists as a consequence of selection of pre-existing telomerase-positive cells during carcinogenesis or through induction of hTERT expression in cells in which it is normally tightly repressed. In support of the latter, chromosome transfer techniques have revealed the presence of genes on normal human chromosomes that are able to extinguish hTERT transcription in cancer cells and induce them to undergo senescence. It is clear that telomerase is obligatory for continuous tumour cell proliferation, clonal evolution and malignant progression. Telomerase therefore represents an attractive target at which to aim new anti-cancer drugs. Results with a variety of telomerase inhibitory strategies in human cancer cells have confirmed that its functional inactivation results in progressive telomere shortening, leading to growth arrest and/or cell death through apoptosis. Promising candidate small molecule inhibitors are beginning to emerge that will form the basis for anti-telomerase drug development.
 ...
PMID:The significance of telomerase activation and cellular immortalization in human cancer. 1243 51

Digestion and detoxification are the two most important functions of the liver, and liver cells always keep a high metabolism level and active vesicular traffic. The malfunction of the vesicular traffic system might be a cause of the abnormal biological behavior of cancerous liver cells. The Ras superfamily is known to regulate various steps of vesicular traffic in eukaryotic cells. It would be significant to determine the change of vesicular transport molecules such as the members of Ras superfamily in carcinogenesis of liver cells. In the present study, we have cloned nine novel genes encoding human small GTPases: RAB1B, RAB4B, RAB10, RAB22A, RAB24, RAB25 ARL5, SARA1, and SARA2, among which the former six belong to the RAB family and the latter three belong to the ARF/SAR1 family. The identification of these new genes has greatly enlarged the pool of the Ras superfamily. It is interesting to find that they are upregulated in most of the 11 hepatocellular carcinoma and 1 cholangiohepatoma cases. Furthermore, the expression in 16 normal human adult tissues, the chromosome loci, and the gene structures of the nine genes are also described. The above findings could be valuable for understanding the vesicular transport system and elucidating the molecular basis of liver cancer carcinogenesis.
 ...
PMID:Identification and characterization of nine novel human small GTPases showing variable expressions in liver cancer tissues. 1245 Feb 15


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>