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

The INK4A gene, a candidate tumor suppressor gene located on chromosome 9p21, encodes two protein products, p16 and p19(ARF). p16 is a negative cell cycle regulator capable of arresting cells in the G1 phase by inhibiting cyclin-dependent kinases 4 (Cdk4) and 6 (Cdk6), thus preventing pRB phosphorylation. p19(ARF) prevents Mdm2-mediated neutralization of p53. Loss of INK4A is a frequent molecular alteration involved in the genesis of several neoplasms, including tumors of neuroectodermal origin. This study investigated the frequency of INK4A gene alterations in a series of malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). INK4A gene and the p19(ARF)-specific exon 1beta were studied in 11 MPNST samples from 8 patients and 7 neurofibromas. Presence of INK4A deletions was assessed by Southern blotting hybridization and by a multiplex polymerase chain reaction (mPCR). INK4A point mutations were examined by single-strand conformation polymorphism (SSCP) and sequencing. The p16 promoter methylation status was determined by PCR amplification of bisulfite-treated DNA. Homozygous deletions of exon 2, thus affecting both p16 and p19(ARF), were identified in MPNSTs from 4 of 8 patients. Deletions, mutations, or silencing by methylation were not identified in the neurofibromas analyzed. Based on our results, we conclude that INK4A deletions are frequent events in MPNSTs and may participate in tumor progression. Silencing of p16 by methylation, which occurs often in several tumor types, is uncommon in MPNSTs.
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PMID:Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas. 1059 15

The Myc family of oncoproteins promote cell growth and are frequently overexpressed in human tumors. However, Myc can also trigger cell death by apoptosis. This is at least in part mediated via the ARF-p53 pathway. Myc activation leads to a selection for inactivation of ARF or p53, allowing cell survival and tumor progression. Restoration of p53-dependent apoptosis by various means is an attractive approach for new cancer therapy.
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PMID:Inactivation of Myc-induced p53-dependent apoptosis in human tumors. 1132 Oct 36

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma, a cancer of which the incidence has been increasing at an alarming rate in Western countries. p16(INK4a) lesions occur frequently in esophageal adenocarcinomas but their role in neoplastic progression is not well understood. We detected 9p21 loss of heterozygosity, p16 CpG island methylation, and p16 mutations in biopsies from 57%, 61%, and 15%, respectively, of 107 patients with BE. In contrast, no mutations were found in p14(ARF) or p15, and methylation was found in only 4% and 13%, respectively. >85% of Barrett's segments had clones with one (p16+/-) or two (p16-/-) p16 lesions. Both p16+/- and p16-/- clones underwent extensive expansion involving up to 17 cm of esophageal mucosa. The prevalence of established biomarkers in BE, such as 17p (p53) loss of heterozygosity, aneuploidy, and/or increased 4N (tetraploid) populations, increased from 0% to 20% to 44% in patients whose biopsies were p16+/+, p16+/-, and p16-/-, respectively (P < 0.001). Barrett's segment lengths also increased with change in p16 status with a median of 1.5, 6.0, and 8.0 cm for patients with p16+/+, p16+/-, and p16-/- biopsies, respectively (P < 0.001). We conclude that most Barrett's metaplasia contains genetic and/or epigenetic p16 lesions and has the ability to undergo clonal expansion, creating a field in which other abnormalities can arise that can lead to esophageal adenocarcinoma.
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PMID:p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium. 1171 61

Lung cancer is the leading cause of cancer death among both men and women, accounting for more than 28% of all cancer deaths. In fact, more people die of lung cancer than of colon, breast, and prostate cancers combined. Although lung cancer is largely induced by smoking, there is strong evidence for genetic susceptibility and gene-environment interactions in the development of lung cancer. Inbred mouse models offer an effective means of identifying candidate lung cancer susceptibility loci since genetic heterogeneity and enormous variation in exposure levels to environmental agents make it difficult to identify lung cancer susceptibility loci in humans. Papg-1 (pulmonary adenoma progression 1) was previously mapped to a region on mouse chromosome 4. This locus contains a candidate gene, Cdkn2a also referred to as Ink4a/Arf, which dually encodes two established tumor suppressors p16(INK4a) and ARF. Cdkn2a became a primary candidate for Papg-1 for two reasons: (1) two haplotypes of mouse Cdkn2a were found to segregate with differential genetic susceptibility to lung tumor progression in mice; and (2) in vitro studies showed that the p16(INK4a) allele from the BALB/cJ mouse had a significantly decreased ability to bind and inhibit CDK6 and to suppress cell growth when compared with the p16(INK4a) allele from the A/J mouse. Here, we report that mice with a heterozygous deficiency for the A/J Cdkn2a allele were significantly more susceptible to lung tumor progression than mice with a heterozygous deficiency for a BALB/cJ Cdkn2a allele, when compared to their respective wild type mice. These results offer strong evidence that naturally occurring variation of p16(INK4a) influences susceptibility to enhance lung tumor progression making it a strong candidate for the lung tumor progression locus, Papg-1.
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PMID:A strong candidate gene for the Papg1 locus on mouse chromosome 4 affecting lung tumor progression. 1218 99

beta-Catenin and its close homologue plakoglobin (gamma-catenin) are major constituents of submembranal cell-cell adhesion sites. In addition, beta-catenin is a key component in the canonical Wnt pathway. Aberrantly activated beta-catenin signaling contributes to cancer progression by inducing [in complex with lymphocyte enhancer factor (LEF)/T-cell factor (TCF)] the transcription of proliferation-related genes such as cyclin D1 and c-myc. Plakoglobin can also activate LEF/TCF-mediated transcription. Excessive beta-catenin signaling in MEF triggers a p53-mediated antiproliferative response by inducing the expression of ARF. We have demonstrated previously that plakoglobin also exerts a tumor-suppressive effect in certain cancer cell lines. To identify genes induced by beta-catenin and plakoglobin, DNA microarray analysis was carried out, and PML was among those genes of which the expression was significantly elevated by both plakoglobin and beta-catenin. Activation of the PML promoter by beta-catenin and plakoglobin was LEF/TCF-independent. We found that PML forms a complex with beta-catenin in cells, and the two proteins colocalize in the nucleus. In addition, PML, p300, and beta-catenin cooperated in transactivation of a subset of beta-catenin-responsive genes including ARF and Siamois but not cyclin D1. Retroviral expression of beta-catenin, plakoglobin, or PML suppressed the tumorigenicity of p53-negative human renal carcinoma cells, thus pointing to a novel antioncogenic response triggered by catenins that is mediated by the induction of PML.
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PMID:PML is a target gene of beta-catenin and plakoglobin, and coactivates beta-catenin-mediated transcription. 1238 61

Xeroderma pigmentosum is an inheritable autosomal recessive DNA repair deficient syndrome characterized by a high predisposition to skin cancers. An elevated proportion of tumors from xeroderma pigmentosum patients harbor ultraviolet-induced mutations (CC:GG > TT:AA tandem transitions) of the p53 and/or the INK4a-ARF genes. Here, we report the clinical and molecular features of a 12 y old xeroderma pigmentosum patient who, in addition to severe cutaneous clinical symptoms, also had three unusual tumors, a mediastinal lymphoblastic lymphoma, an atypical fibroxanthoma, and an epithelioid hemangioma. Single strand conformation polymorphism and sequencing analysis of the p53 and INK4a-ARF genes were carried out in DNA from normal skin and different tumors (four actinic keratosis, two microinvasive squamous cell carcinomas, one basal cell carcinoma, and one atypical fibroxanthoma) from the patient. After characterization of the xeroderma pigmentosum C complementation group, we found unexpectedly that this patient also carried a germline mutation of the INK4a-ARF locus affecting the p16INK4A reading frame. Three different somatic mutations that all harbor the signature of ultraviolet light (two of p16INK4A and one of p53) were also detected in the basal cell carcinoma. We hypothesize that the germline mutation of p16INK4A, in association with the nucleotide excision repair defect, could explain the patient's unusual phenotype. Furthermore, this study confirms that concomitant somatic mutations of INK4a-ARF and p53 occur in some xeroderma pigmentosum associated tumors, and seem to accumulate during tumor progression rather than the initiation step.
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PMID:Germline and somatic mutations of the INK4a-ARF gene in a xeroderma pigmentosum group C patient. 1248 39

Multiplex methylation-sensitive PCR was employed in studying the methylation of CpG islands in the RB1, p16/CDKN2A, p15/CDKN2B, p14/ARF, CDH1, HIC1, and N33 5' regions in non-small cell lung cancer (51 tumors). Methylation was observed for the two suppressor genes involved in controlling the cell cycle through the Cdk-Rb-E2F signaling pathway, RB1 (10/51, 19%) and p16 (20/51, 39%). The highest methylation frequencies were established for CDH1 (72%) and HIC1 (82%). The CpG islands of p14 and p15 proved to be nonmethylated. At least one gene was methylated in 90% (46/51) tumors and no gene, in 10% (5/51) tumors. In addition, the genes were tested for methylation in peripheral blood lymphocytes of healthy subjects. Methylation frequency significantly differed between tumors and normal cells in the case of RB1, p16, CDH1, HIC1, and N33. Gene methylation frequency was tested for association with histological type of the tumor and stage of tumor progression. Methylation index of a panel of tumor suppressor genes was established for groups of tumors varying in clinical and morphological parameters.
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PMID:[Profile of methylation of certain tumor growth suppressing genes in non-small cell lung cancer]. 1471 93

A role for the NF-kappaB family of transcription factors as tumor promoters is firmly established. However, other data suggest that NF-kappaB can also inhibit tumor growth. Moreover, NF-kappaB activity is modulated by tumor suppressors, such as p53 and ARF, whereby NF-kappaB subunits repress, rather than activate, the expression of tumor-promoting genes. This suggests a dual function of NF-kappaB during tumor progression - in the early stages, NF-kappaB inhibits tumor growth but, as further mutations lead to a loss of tumor suppressor expression, the oncogenic functions of NF-kappaB become unleashed, allowing it to actively contribute to tumorigenesis. Here, I discuss this hypothesis, its implications for NF-kappaB function, and how this might influence the use of NF-kappaB-based anticancer therapies.
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PMID:NF-kappaB: tumor promoter or suppressor? 1510 37

The modulation of Bmi-1 is observed in several tumor tissues, and its heightened protein level is suspected to be involved in tumorigenesis by acting as a transcriptional repressor in the INK4a/ARF locus. To elucidate the modulation of Bmi-1 in invasive ductal breast cancers, we examined its transcript and protein levels. The bmi-1 mRNA level by reverse transcription-polymerase chain reaction (RT-PCR) showed that it was significantly up-regulated in 28 specimens out of 33 breast carcinoma tissues compared with those of non-neoplastic tissues just adjusted to tested specimens. Immunohistochemical staining for Bmi-1 also showed that 44 specimens out of 71 breast carcinoma tissues (62%) had strong positive signals with a more intense staining pattern in the invading fronts than in the central portions of primary invasive breast cancers. Univariate and multivariate analyses showed that a high level of Bmi-1 expression was significantly correlated with axillary lymph node metastases and positive estrogen receptor status. These findings suggested that Bmi-1 might be involved in the tumor progression and metastasis of invasive ductal breast cancer.
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PMID:Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. 1545 93

Immortalized p19(ARF) null hepatocytes (MIM) feature a high degree of functional differentiation and are susceptible to transforming growth factor (TGF)-beta driven growth arrest and apoptosis. In contrast, polarized MIM hepatocytes expressing hyperactive Ha-Ras continue proliferation in cooperation with TGF-beta, and adopt an invasive phenotype by executing an epithelial to mesenchymal transition (EMT). In this study, we analyzed the involvement of Ras subeffectors in TGF-beta mediated hepatocellular EMT by employing MIM hepatocytes, which express Ras mutants allowing selective activation of either mitogen-activated protein kinase (MAPK) signaling (V12-S35) or phosphoinositide 3-OH (PI3)3 kinase (PI3K) signaling (V12-C40). We found that MAPK signaling in MIM-S35 hepatocytes was necessary and sufficient to promote resistance to TGF-beta mediated inhibition of proliferation in vitro and in vivo. MIM-S35 hepatocytes showed also PI3K activation during EMT, however, MAPK signaling on its own protected hepatocytes from apoptosis. Yet, MIM-C40 hepatocytes failed to form tumors and required additional MAPK stimulation to overcome TGF-beta mediated growth arrest. In vivo, the collaboration of MAPK signaling and TGF-beta activity drastically accelerated the cell-cycle progression of the hepatocytes, leading to vast tumor formation. From these data we conclude that MAPK is crucial for the cooperation with TGF-beta to regulate the proliferation as well as the survival of hepatocytes during EMT, and causes the fatal increase in hepatocellular tumor progression.
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PMID:Integration of Ras subeffector signaling in TGF-beta mediated late stage hepatocarcinogenesis. 1570 98


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