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

Abnormalities in the p53 gene have been regarded as the most consistent genetic abnormalities detected in head and neck squamous cell carcinogenesis. Two new members of the p53 gene family, p73 and p63, have recently been identified. We investigated the expression of the two N-terminal p63 isoforms (TA and deltaN isoforms) in human primary well-differentiated buccal squamous cell carcinoma. Both TAp63 and deltaNp63 isoforms were detected in the basal/suprabasal layers of all of the five specimens of normal buccal mucosa. The deltaNp63 isoform was found in all of the 23 specimens of human primary well-differentiated buccal carcinoma whereas TAp63 isoform was absent in 18 (78.3%) of the 23 specimens. The immunostaining patterns of both TAp63 and deltaNp63 isoforms were similar in that the p63 positivity was noted mainly in the peripheral cells of tumor nests whereas negative staining was observed in the areas with keratin pearl formation. A higher number of T3-T4 patients and patients with recurrence showed negative staining of TAp63 than T1-T2 patients and patients without recurrence but the difference was not statistically significant. These results suggested that specific p63 isoforms were associated with human oral squamous cell carcinogenesis. The deltaNp63 isoforms might be involved in epithelial differentiation and proliferation in human oral carcinogenesis whereas there was evidence for a possible role of TAp63 under-expression in human oral tumorigenesis.
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PMID:Expression of p63 (TA and deltaN isoforms) in human primary well differentiated buccal carcinomas. 1518 14

p63, a recently identified member of the p53 gene family, plays an important role in human tissue functions. We examined the pattern of p63 expression in human esophageal squamous cell carcinomas including early-stage cancers, and its clinicopathological significance. Immunoreactivity for p63 was detected in 96.9% (63/65) esophageal squamous cell carcinomas. Diffuse p63 expression was seen in 75.4% (49/65). p63 was detected not only in the in situ carcinomatous components or intramucosal carcinomas, but also in the invasive carcinomatous parts of the p63-positive cases. There were no significant correlations between p63 expression and clinicopathological features, such as depth of tumor invasion, tumor differentiation, lymph node metastasis and venous/lymphatic invasion. We also analyzed the relationship between p63 and p53 expression in esophageal squamous cell carcinomas. These results suggest that the p63 gene, as well as the p53 gene, play a major role in the carcinogenesis of human esophageal squamous cells and in the growth of the carcinoma.
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PMID:Ubiquitous p63 expression in human esophageal squamous cell carcinoma. 1525 60

Perp is a target of the p53 tumor suppressor involved in the DNA damage-induced apoptosis pathway. In addition, Perp is a target of the p53-related transcription factor p63 during skin development, where it participates in cell-cell adhesion mediated through desmosomes. Here we test the role of Perp in tumorigenesis in a two-step skin carcinogenesis model system. We find that mice lacking Perp in the skin are resistant to papilloma development, displaying fewer and smaller papillomas than wild-type mice. Proliferation levels, apoptotic indices and differentiation patterns are similar in the skin of treated Perp-deficient and wild-type mice. Instead, impaired adhesion through aberrant desmosome assembly may explain the diminished tumor development in the absence of Perp. These studies indicate that in certain contexts, Perp is required for efficient carcinogenesis and suggest a role for intact cell-cell adhesion in supporting tumor development in these settings.
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PMID:Mice lacking the p53/p63 target gene Perp are resistant to papilloma development. 1606 34

p63 is critical for squamous development and exists as multiple isotypes of two subclasses, TA and DeltaN. DeltaNp63 isotypes can antagonize transcription by TAp63 and p53, and are highly expressed in squamous cell cancers. Using mouse keratinocytes as a biological model of squamous epithelium, we show that multiple p63 isotypes, DeltaN- and TA-containing, are expressed and differentially modulated during in vitro murine keratinocyte differentiation. DeltaNp63alpha declines with Ca2+-induced differentiation, while a smaller DeltaN-form, DeltaNp63s, persists, suggesting unique functions of the two DeltaN-forms. To investigate the impact of dysregulated p63 expression that is observed in cancers and to define the biological contribution of the different domains of the p63 isotypes, DeltaNp63alpha, DeltaNp63p40, TAp63alpha, TAp63gamma or beta-galactosidase were overexpressed in primary murine keratinocytes. Microarray, RT-PCR and western blot analyses revealed that overexpression of DeltaNp63p40, which lacks the entire alpha-tail present in DeltaNp63alpha, permits expression of a full panel of differentiation markers. This is in contrast to overexpression of the full-length DeltaNp63alpha, which blocks induction of keratin 10, loricrin and filaggrin. These findings support a role for the alpha-tail of DeltaNp63alpha in blocking differentiation-specific gene expression. Overexpression of either TAp63 isotype permits keratin 10 and loricrin expression, thus the alpha-terminus requires the cooperation of the DeltaN domain in blocking early differentiation. However, both TA isotypes block filaggrin induction. The DeltaN-terminus is sufficient to maintain keratinocytes in a proliferative state, as both DeltaN forms block Ca2+-mediated p21WAF1 induction and S-phase arrest, while sustaining elevated PCNA levels. No alteration in cell cycle regulation was observed in keratinocytes overexpressing TAp63alpha or TAp63gamma. Clarifying the functional distinctions between p63 isotypes and domains will help to elucidate how their dysregulation impacts tumor biology and may suggest novel therapeutic strategies for modulating behavior of tumor cells with altered expression of p53 family members.
Carcinogenesis 2006 Jan
PMID:Unique domain functions of p63 isotypes that differentially regulate distinct aspects of epidermal homeostasis. 1608 16

For a quarter of a century the gene p53 has attracted close attention of scientists who deal with problems of carcinogenesis and maintenance of genetic stability. Multicellular organisms on our planet owe their rich evolution in many respects to the ability of this gene to protect cells from oncogenic transformation and harmful changes in DNA. A relatively recent discovery of structural p53 homologs, the genes p63 and p73, which seem to have more ancient roots, has roused keen interest in their function. Do they carry out oncosuppressor functions in partnership with p53 or do they possess their own specific functions? This review analyzes data on p53, p63, and p73 functional activity at the levels of the molecule, cell, and whole organism with the accent on examination of specific p63/p73 targets indicating a unique role of these genes in control of developmental processes.
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PMID:The p53 gene family: control of cell proliferation and developmental programs. 1626 65

P63 is a member of the p53 family, which plays a role in the differentiation of urothelium and is supposed to play a role in urothelial carcinogenesis. P53 and MIB-1 are recognised in many studies as predictive markers of progression, but few studies in the literature have examined p63. The aims of our study were to explore the expression of p63 in bladder carcinomas and to compare this expression to p53 and MIB-1, as well as to stage and grade. Tissue microarrays were performed on 158 urothelial carcinomas (56 pTa, 45 pT1 and 57>or=pT2). Immunohistochemical studies were performed with p63, p53 and MIB-1 antibodies. In our study we observed that p63 immunostaining is present in all cell layers in papillary urothelial neoplasm of low malignant potential (PUNLMP), but partially lost in non-invasive papillary urothelial carcinoma low grade (NILGC) and in pT1/>or=pT2 bladder cancers. P53 and MIB-1 displayed lower expression in PUNLMP/NILGC vs non-invasive papillary urothelial carcinoma high grade (NIHGC)/pT1, but there was no correlation between the expression of p63, p53 and MIB-1. Our study demonstrates that p63 expression distinguishes between PUNLMP/NILGC and NIHGC/pT1 (p=4.10(5)). A statistical difference disserving pTa and pT1/>or=pT2 with a statistical significance (p<10(-6)) could also be observed. P63 should be considered as an additional biomarker that might help pathologists to classify their patients.
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PMID:Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder carcinoma. A tissue microarray study of 158 cases. 1628 78

Understanding the stages of cell differentiation in the normal prostate epithelium is essential for the identification of the cell type(s) involved in prostatic carcinogenesis. Prostate glands are composed of three types of epithelial cells (i.e., basal, secretory and neuroendocrine) but the hierarchical relations among these cell types have been long controversial. We have recently developed a novel system to define prostate epithelial cell lineages in vivo. We find that, during normal prostate organogenesis, terminally differentiated secretory cells derive from p63-positive basal cells, which thus represent/include prostate stem cells. Future studies will determine if p63-positive basal cells retain stem cells capabilities in the adult prostate epithelium.
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PMID:Defining cell lineages in the prostate epithelium. 1635 39

The p63 gene is a member of the p53 family that plays a role in cell differentiation, development and carcinogenesis. The relationship between p63 expression and the prognosis of esophageal squamous cell carcinoma (ESCC) remains unknown. The present study examines the clinical impact of p63 in patients with ESCC. Resected specimens from 180 patients with ESCC were immunostained for p63 and p53. After establishing a cut-off value for p63 expression, we statistically examined its clinical impact and relationship to p53 expression. At a 50% cut-off value for p63 expression, the 5-year overall survival was significantly longer in p63-positive (46.4%) than -negative patients (11.1%, p=0.05). Among the 180 ESCC patients, 171 (95.0%) were p63 immunoreactive and only 9 (5.0%) were negative. The correlation between p63 status and clinicopathological parameters was not significant, although p63-negativity tended to correlate with distant metastasis (p=0.06) and clinical stage (p=0.08). Univariate analysis demonstrated significant correlations between patient survival and tumor diameter, depth of invasion, lymphatic invasion, vascular invasion, lymph node metastasis and distant metastasis. The survival of patients who did not express p63 and p53 was obviously unfavorable (p=0.03). Multivariate analysis revealed that only lymph node metastasis was a critical independent prognostic marker for overall survival (p=0.0015). Expression of p63 was not an independent prognostic factor for overall survival in this study (p=0.69). These data suggest that, although a reduced expression of p63 is infrequent, it has a prognostic impact upon patients with ESCC.
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PMID:Reduced expression of p63 has prognostic implications for patients with esophageal squamous cell carcinoma. 1639 49

A novel human mammary epithelial cell line, HME348, was established from benign breast tissue from a 44-year-old germ-line BRCA2 mutation carrier with a history of stage 1 breast cancer. Mutation analysis showed that the patient had a known 6872del4 BRCA2 heterozygous mutation. The human mammary epithelial cells passaged in culture exhibited cellular replicative aging as evidenced by telomere shortening, lack of telomerase activity, and senescence. Ectopic expression of telomerase (hTERT) reconstituted telomerase activity in these cells and led to the immortalization of the cells. When grown on glass, the majority of immortalized HME348 cells expressed ESA and p63 with a small population also expressing EMA. In three-dimensional Matrigel culture, HME348 cells formed complex branching acini structures that expressed luminal (EMA, CK18) and myoepithelial (p63, CALLA, CK14) markers. Three clones derived from this culture were also p63(+)/ESA(+)/EMA(+/-) on glass but formed similar acinar structures with both luminal and myoepithelial cell differentiation in Matrigel confirming the mammary progenitor nature of these cells. Additionally, the experimentally immortalized HME348 cells formed acini in cleared mammary fat pads in vivo. As this is the first report establishing and characterizing a benign human mammary epithelial cell line derived from a BRCA2 patient without the use of viral oncogenes, these cells may be useful for the study of BRCA2 function in breast morphogenesis and carcinogenesis.
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PMID:Telomerase immortalization of human mammary epithelial cells derived from a BRCA2 mutation carrier. 1654 10

We have used a recently described model in which a ras oncogene is expressed in cytokeratin 5 (K5)-expressing cells on doxycycline administration to explore the effects of this oncogene in salivary glands of adult mice. Inducible expression of a mutated K-ras gene under the control of the K5 promoter led to the development of hyperplastic and dysplastic epithelial lesions and carcinomas, with an incidence of 100% and a minimum latency of a week. All major salivary glands were affected, as well as a set of previously undescribed buccal accessory salivary glands located on the apex of the masseter muscle, close to the oral angle. The tumors appear to arise from the cytokeratin 5-positive basal cell compartment. Myoepithelial cells participated in the hyperplasias but not in carcinomas, because the tumors are negative for smooth muscle actin. Carcinomas did not accumulate immunoreactive p53 but are positive for p63, as assayed by immunohistochemistry using an antibody against the N terminus of DeltaN p63, a splice variant of p63 that can inhibit p53 transcriptional activity. In this study, we provide evidence that the ras oncogene, targeted to a specifically sensitive cell compartment within the salivary glands, can trigger a series of event that are sufficient for full carcinogenesis.
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PMID:Rapid development of salivary gland carcinomas upon conditional expression of K-ras driven by the cytokeratin 5 promoter. 1665 31


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