Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pl6INK4a/MTS1 (p16) gene encodes a specific inhibitor of cyclin-dependent kinase (CDK)4 and CDK6. The p16 gene is frequently mutated or deleted in many types of cancer cell lines as well as in certain types of primary tumors. p16 knockout mice are viable but predisposed to sarcoma and B-cell lymphoma. To investigate the role of p16 in human soft-tissue sarcoma tumor progression, we examined the p16 gene by Southern blot analysis and PCR sequencing in 30 pairs of primary soft-tissue sarcomas and autologous normal tissue. Only one tumor sample showed possible rearrangement of the p16 gene. In contrast, Western blot analysis of the p16 protein in 20 pairs of samples showed decreased p16 expression in only 20% of the tumors but elevated p16 expression in 40% of the tumors when compared with the autologous normal controls. Overexpression of p16 was not concomitant with loss of the RB protein as is found in several other types of cancers, because more than one-half of the tumors with increased p16 expression also had high levels of RB protein. On the other hand, the p16 target protein CDK4 was overexpressed in at least 60% of the tumors. In the majority of cases, CDK4 overexpression accompanied elevated p16 and/or RB levels. Our results suggest that: (a) alteration of the p16 gene is infrequent in primary soft-tissue sarcoma; (b) Cdk4 may act as an oncogene in soft-tissue sarcoma; and (c) elevated p16 and RB levels might be the result of compensatory up-regulation of these proteins to counteract CDK4 overexpression in these tumors. Our results also suggest that it is more informative to examine aberrations in the "p16-CDK4/cyclin D-RB" pathway than to selectively examine individual components in this pathway when investigating genetic changes involved in human malignancy.
 ...
PMID:Infrequent mutation of the p16/MTS1 gene and overexpression of cyclin-dependent kinase 4 in human primary soft-tissue sarcoma. 956 3

Cancer is a genetic disease resulting from an accumulation of genetic abnormalities in various regulatory genes. Most studies on genetic alterations in human breast cancer have involved primary tumors. The possible involvement of specific tumor suppressor genes in the later stages of cancer progression is poorly documented. We investigated allelic losses associated with breast cancer progression by analyzing 55 polymorphic markers on 11 autosomal chromosomes in a series of 49 relapses (23 local recurrences and 26 distant metastases). All of the loss of heterozygosity (LOH) regions reported in primary breast tumors were frequent in both series of relapses. These results suggest that the allelic losses that are common to the different series of samples occur very early during tumor progression. This study points to candidate metastasis-related genes targeted by LOH on chromosome arms 3p21.3, 16q22.2-23.2, and, possibly, 7q31 but provides no clear evidence of LOH affecting previously described metastasis-related genes such as NME1, MTS1, and TSG101.
 ...
PMID:Location of several putative genes possibly involved in human breast cancer progression. 960 47

In esophageal carcinoma, individual genetic alterations of cyclins, cyclin-dependent kinase inhibitors, and final effectors of the G1-to-S transition have been documented. Our aim was to design a comprehensive analysis of the role and clinical significance of some critical genes, namely cyclin D1, MTS1, and Rb. To this end, cyclin D1 gene amplification and protein accumulation, Rb gene allelic loss and protein expression, and MTS1 gene mutation and DNA methylation were investigated in a series of 74 esophageal carcinomas. Cyclin D1 amplification was documented in 17 of 55 (31 %) cases, being a feature of squamous cell type (14 of 17 amplified cases). Cyclin D1 accumulation significantly correlated with lymph node metastasis (p < 0.02), advanced tumor stage (p < 0.05), and a reduced overall survival rate (p < 0.03). Rb gene loss of heterozygosity occurred in 14 of 39 (36%) informative cases and was associated with an unfavorable survival rate (p < 0.01). MTS1 gene mutations were detected in 2 adenocarcinomas only; gene methylation was observed in 17 of 72 cases (24%) without any correlations with the variables investigated. A direct association between cyclin D1 and Rb gene accumulation (p < 0.0005) and an inverse one between RB loss of heterozygosity and MTS1 abnormalities (p < 0.05) emerged from this study. These results have important clinical implications because both cyclin D1 and Rb gene deregulation are significantly related to an unfavorable survival rate. In addition, cyclin D1 amplification is associated with esophageal carcinoma of squamous cell type, being totally absent in adenocarcinomas (p < 0.01). The combined evaluation of these genes also demonstrates that molecular abnormalities of genes belonging to the same pathway are mutually exclusive and unnecessary for the neoplastic transformation and tumor progression.
 ...
PMID:Cell cycle-related gene abnormalities and product expression in esophageal carcinoma. 975 49

Esophageal squamous cell carcinoma (ESCC) has high malignant potential with a poor outcome. Lymph node metastasis is the most useful indicator for predicting the outcome of ESCC. The p16/MTS1/CDKN2 gene and the cyclin D1/PRAD-1 gene cooperatively regulate CDK4-mediated phosphorylation of RB protein in the cell cycle. We immunohistochemically detected p16, cyclin D1, and RB expressions in both primary lesions and metastatic lymph nodes in ESCC. Among the 50 ESCC primary lesions, 24 (48%) were positive for p16, while 26 (52%) were negative for p16. Sixteen (32%) were p16-positive, 34 (68%) were p16-negative among the 50 ESCC metastatic lymph nodes. Eight cases (16%) were p16-positive in primary lesion and p16-negative in lymph node, however, no cases that was p16-negative in the primary tumor exhibited p16-positivity in metastatic lymph nodes (p < 0.0001). Seventeen (34%) of the 50 ESCC primary lesions were cyclin D1-positive, while 33 (66%) were cyclin D1-negative. Twenty-four (48%) were cyclin D1-positive, 26 (52%) were cyclin D1-negative among the 50 metastatic lymph nodes. Five cases (10%) were cyclin D1-positive in primary lesion and cyclin D1-negative in lymph node, and 12 cases (24%) were cyclin D1-negative in primary lesion and cyclin D1-positive in lymph nodes. Nine cases (18%) were RB-negative in 50 primary lesions, and the rate of loss of RB expression in metastatic lymph nodes was not markedly higher than in primary lesions. Thirty-nine (78%) of 50 primary lesions and 46 (92%) of 50 metastatic lymph nodes had altered expression of at least one of the three G1 control genes. Tumor cell with disruption of these cell cycle regulators can get a growth advantage and metastatic potential during tumor progression, especially p16/CDKN2 alterations may be associated with lymph node metastasis in ESCC. These results also suggest that tumor cells in metastatic lymph nodes may have more aggressive proliferation and higher malignant potential than tumor cells in primary lesions.
 ...
PMID:Further evidence that altered p16/CDKN2 gene expression is associated with lymph node metastasis in squamous cell carcinoma of the esophagus. 1129 92

Based on the concept that tumor suppressor genes are involved in the pathogenesis of urinary bladder carcinogenesis, we analysed the mRNA expression of the retinoblastoma (Rb) and p16 (CDKN2, INK4A, MTS1) genes as well as of the proto-oncogene cyclin D-dependent kinase 4 (CDK4) in 71 transitional cell carcinomas (TCC) of the urinary bladder in relation to the tumor grades and stages, and with reference to certain lifestyle and occupational risk factors. Using real-time quantitative reverse transcription-polymerase chain reaction, high-stage muscle invasive TCC expressed the Rb, p16 and CDK4 mRNA at lower levels than low-stage superficial cancers, indicating down-regulation to be linked with tumor progression. The drop of the expression in the group of grade 2 TCC when invading the muscle layer compared to grade 2 carcinomas with a superficial pattern of growth is considered to represent a key event in promoting urothelial carcinogenesis in this subset of carcinomas. The protein expression of the Rb gene evaluated by immunohistochemistry proved to be closely related to the tumor grades and stages as well as to the mRNA expression, high-grade and high-stage TCC disclosing a lower rate of positive immunoreactivity than low-grade and low-stage carcinomas. The p16 protein product was expressed at a lower level in grade 3 than in grade 1 TCC, but there was no correlation with the tumor stages or the mRNA expression. TCC with loss of heterozygosity (LOH) at the INK4A region showed a decreased expression of p16 mRNA compared to those without an allelic loss. Tobacco smoke was not identified to substantially modulate the Rb/p16/CDK4 pathways, except for a ten-fold elevated mRNA expression of the p16 gene in TCC of light compared to heavy smokers. Heavy coffee consumption was associated with a reduced expression of CDK4 mRNA. Among occupational exposures, TCC of patients in contact with stone dust, paints and lacquer, plastics, wood and wood preservers and chemical solvents and adhesives displayed altered partly elevated, partly reduced levels of Rb, p16 and CDK4 mRNA compared to non-exposed subjects. Although the underlying molecular-genetic pathways are not yet fully understood, the current results suggest functional reduction of the tumor suppressor genes Rb and p16 to be associated with progression of bladder cancer to a more malignant and aggressive behaviour.
 ...
PMID:Altered mRNA expression of the Rb and p16 tumor suppressor genes and of CDK4 in transitional cell carcinomas of the urinary bladder associated with tumor progression. 1516 Oct 57

P16(INK4A) (also known as P16 and MTS1), a protein consisting exclusively of four ankyrin repeats, is recognized as a tumor suppressor mainly because of the prevalence of genetic inactivation of the p16(INK4A) (or CDKN2A) gene in virtually all types of human cancers. However, it has also been shown that an elevated level of expression (upregulation) of P16 is involved in cellular senescence, aging, and cancer progression, indicating that the regulation of P16 is critical for its function. Here, we discuss the regulatory mechanisms of P16 function at the DNA level, the transcription level, and the posttranscriptional level, as well as their implications for the structure-function relationship of P16 and for human cancers.
 ...
PMID:Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. 2161 50

DNA methylation is a key diagnostic maker for genetic disease, cancer progression and pharmcogenomics. So far various techniques have been developed for DNA methylation assay, but most of them are laborious and time-consuming. Here we develop a simple and highly sensitive DNA methylation assay based on single base extension reaction and surface enhanced Raman spectroscopy (SERS). In the presence of methylated DNA, gold nanoparticle-modified capture probe can couple with a cyanine 5-deoxyribonucleoside triphosphate (cy5-dGTP) through single base extension reaction, and generates a high SERS signal after further addition of gold nanoparticles to increase the local electromagnetic field. While in the presence of unmethylated DNA, gold nanoparticle-modified capture probe cannot couple with cy5-dGTP due to the presence of a mismatch base, and no SERS signal is observed. This single base extension reaction-based SERS can determine methylated DNA with a detection limit of 3 pM, and can even distinguish as low as 1% methylation level in tumor suppressor gene CDKN2/p16/MTS1 (p16) from the mixtures. Notably, the sensitivity of this assay has improved by 5 orders of magnitude as compared to reported gold nanoparticle-based colorimetric assay, and by 2 orders of magnitude as compared to microarray-based methylation-sensitive single nucleotide primer extension assay (Ms-SNuPE). This method might be further applied to detect the methylation status in tumor-linked genes for cancer diagnosis.
 ...
PMID:Single base extension reaction-based surface enhanced Raman spectroscopy for DNA methylation assay. 2212 82


<< Previous 1 2