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

TP63, a member of the TP53 gene family, encodes two groups of three isoforms (alpha, beta and gamma). The TAp63 isoforms act as transcription factors. The DeltaNp63 isoforms lack the main transcription activation domain and act as dominant-negative inhibitors of transactivation (TA) isoforms. To clarify the role of these isoforms and to better understand their functional overlap with p53, we ectopically expressed each p63 isoform in the p53-null hepatocellular carcinoma cell line Hep3B. All TA isoforms, as well as DeltaNp63alpha, had a half-life of <1 h when transiently expressed and were degraded by the proteasome pathway. The most stable form was DeltaNp63gamma, with a half-life of >8 h. As expected, TA isoforms differed in their transcriptional activities toward genes regulated by p53, TAp63gamma being the most active form. In contrast, DeltaNp63 isoforms were transcriptionally inactive on genes studied and inhibited TA isoforms in a dose-dependent manner. When stably expressed in polyclonal cell populations, TAp63beta and gamma isoforms were undetectable. However, when treated with doxorubicin (DOX), p63 proteins rapidly accumulated in the cells. This stabilization was associated with an increase in phosphorylation. Strikingly, in DOX-treated polyclonal populations, increase in TAp63 levels was accompanied by overexpression of DeltaNp73. This observation suggests complex regulatory cross talks between the different isoforms of the p53 family. In conclusion, p63 exhibits several transcriptional and stress-response properties similar to those of p53, suggesting that p63 activities should be taken into consideration in approaches to improve cancer therapies based on genotoxic agents.
Carcinogenesis 2008 Feb
PMID:Properties of the six isoforms of p63: p53-like regulation in response to genotoxic stress and cross talk with DeltaNp73. 1804 90

Mutation of the p53 gene is a common event in human cancer. Interestingly, p53 mutation is uncommon in nasopharyngeal carcinoma (NPC). The DeltaNp63 has been postulated to have a dominant-negative effect on the function of the p53 gene and may play a role in the pathogenesis of nasopharyngeal carcinoma. Immortalization is a common property of cancer cells and is believed to be an early event in carcinogenesis. At present, the relationship between DeltaNp63 and immortalization is poorly understood. In this study, we defined the expression profile of p63 and its various isoforms in primary and immortalized nasopharyngeal epithelial cells. Also, we elucidated some events regulating the expression of p63. Elevated expression of p63 was generally detected in both primary and immortalized nasopharyngeal epithelial cells at their proliferation stage and the predominant isoform of p63 expressed was DeltaNp63alpha. p63 expression was suppressed upon cellular senescence of primary nasopharyngeal epithelial cells and induction of terminal differentiation in immortalized nasopharyngeal epithelial cells. Expression of DeltaNp63 alone was able to drive clonal proliferation in primary nasopharyngeal cells in culture while downregulation of DeltaNp63 induced cellular apoptosis. All these results support a role of DeltaNp63 in proliferation and immortalization which facilitates pathogenesis of nasopharyngeal carcinoma. TGFbeta and retinoic acid downregulated the expression of p63 in immortalized nasopharyngeal epithelial cells and may play a role in regulating differentiation in squamous epithelial cells with potential applications in prevention and treatment of nasopharyngeal carcinoma.
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PMID:Regulation of p63 expression in primary and immortalized nasopharyngeal epithelial cells. 1881 84

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer which is twice as lethal as melanoma as more than one-third of MCC patients will die from this cancer. Although MCC, which primarily affects elderly and immune suppressed individuals, is very rare to date, its incidence is rapidly increasing. In contrast to the immense progress that has been made in the elucidation of the molecular pathogenesis of other cancer entities, until recently there were no clear-cut indications which events drive the carcinogenesis of MCC. Important findings published last year have changed this radically. Hypermethylation of the p14(ARF) promoter and a striking correlation between expression of p63 and the clinical course of MCC have been reported. Most important, however, is the discovery that MCC development in the majority of cases is preceded by the integration of genomic sequences of the hitherto unknown Merkel cell polyomavirus (MCPyV). Now a fundamental improvement in the understanding of MCC pathogenesis as well as the development of new therapeutic approaches based on this knowledge appear to be possible within the near future.
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PMID:Molecular pathogenesis of Merkel cell carcinoma. 1940 Aug 30

Actinic cheilitis (AC) is a potentially malignant disorder, which can present degrees of epithelial dysplasia, and may even evolve into lip squamous cell carcinoma (LSCC). Since p63 is a protein homologous to p53, which can be associated with tumorigenesis in epithelial tissues, this study aims to evaluate it in AC and LSCC, in the hopes to estimate the biological behavior of these lesions. Forty AC lesions and sixty-five cases of LSCC were quantitatively analyzed by immunohistochemistry, using anti-p63 antibody with ten cases of normal lip mucosa used as a control group. In all AC and LSCC cases studied, it was possible to detect the presence of the p63 protein. There was no statistically significant difference between immunostained cells and degree of epithelial dysplasias, nor between the LSCC grading malignancy. Nevertheless, p63 immunoexpression showed to be significantly correlated with AC and LSCC lesions as compared to normal lip epithelium. The results indicate that p63 protein is consistently expressed in AC and LSCC, and might be of help in the differential diagnosis between normal and dysplastic/neoplastic epithelium, although the evaluation using a primary antibody to all isotypes did not prove to be a risk biomarker during lip carcinogenesis. Thus, the production of antibodies for the six different p63 isotypes is urged, since in isolation they can have predictive value, mainly the DeltaNp63 isoforms.
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PMID:p63 Immunoexpression in lip carcinogenesis. 1952 17

The development of prostate cancer is believed to be a multistep process, progressing sequentially from normal epithelium, to prostatic intraepithelial neoplasia (PIN) and, finally, to invasive neoplasia. Malignant stem cells within the basal cell layer of the prostatic epithelium are believed to play an important role in the failure of androgen-ablation therapy that occurs in the most advanced form of prostate cancer. The aim of the present study was to immunohistochemically characterize the lesions of canine PIN. Prostatic tissue from five dogs with PIN was compared with normal prostate tissue from nine further dogs. There was an increase in the number of basal epithelial cells in lesions consistent with PIN as defined by expression of the nuclear protein p63. These lesions had elevated expression of proliferating cell nuclear antigen (PCNA) and heterogeneous labelling for the nuclear androgen receptor (AR). These findings suggest that the basal cells present in PIN may play a role in canine prostate carcinogenesis and that the proliferation of these cells occurs despite the heterogeneous expression of the AR.
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PMID:Immunohistochemical characterization of canine prostatic intraepithelial neoplasia. 1964 31

Osteopontin (OPN) is a secreted glycoprotein implicated to function in cancer development and metastasis. Although elevated expression of OPN are observed in cancer cells of various types, in some cases, only the cells in the stromal region surrounding the tumor express OPN, suggesting distinct functional roles for this protein derived from host cells and from cancer cells. To provide a model for addressing the functions and mechanisms of host-derived OPN in cancer progression and metastasis, a cutaneous squamous cell carcinoma cell line (ONSC) that lacks the OPN gene, Spp1, was established. This line of cells was derived from a squamous cell carcinoma that developed in a female, OPN-null mouse subjected to two-stage skin carcinogenesis. Morphologically, ONSC cells resemble epithelial cells, and they express the epithelial markers, K1, K14, and p63, as confirmed by immunohistochemical analyses. Genomic analyses indicate the presence of mutated H-Ras and p53 genes. ONSC cells form colonies in soft agar and, subcutaneously injected into athymic nude mice, develop into squamous cell carcinomas that metastasize to the lungs. Lacking OPN expression, these squamous cell carcinoma cells provide a model to address the function of host OPN in the context of cancer progression and metastasis.
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PMID:Establishment and characterization of an osteopontin-null cutaneous squamous cell carcinoma cell line. 1991 34

Tissue remodeling or regeneration is believed to initiate from multipotent stem and progenitor cells. We report here the establishment of two spontaneously immortalized adult non-tumorigenic human prostate epithelial cell lines, NHPrE1 and BHPrE1. NHPrE1 (CD133(high)/CD44(high)/OCT4(high)/PTEN(high)) was characterized as a putative progenitor cell, and BHPrE1 (p63(high)/p53(high)/p21(WAF1)(high)/RB(high)) was characterized as a putative epithelial intermediate cell. Genomic analysis demonstrated an abnormal karyotype with genomic rearrangements including PTEN amplification in NHPrE1 and CTNNB1 (beta-catenin) amplification in BHPrE1 cells. Embedded three-dimensional culture of NHPrE1 showed greater branching than BHPrE1. A tissue recombination-xenografting model was utilized to compare remodeling of human prostatic tissues in vivo. A series of tissue recombinants, made by mixing different ratios of human prostatic epithelial cells and inductive rat urogenital sinus mesenchyme, were grafted to the renal capsule of severe combined immunodeficient mice. Both cell lines were able to regenerate benign secretory ductal-acinar architecture in vivo, containing intact basal and luminal epithelial layers confirmed by the expression of appropriate CK profiles. Prostate-specific antigen, 15-lipoxygenase-2, androgen receptor, and NKX3.1 proteins were appropriately expressed in the regenerated epithelia. Regeneration of benign prostatic glandular structures could be achieved using as few as 10 NHPrE1 cells, whereas 200,000 BHPrE1 cells were required to achieve prostatic architecture. This suggests a greater proportion of progenitor/stem cells in NHPrE1 than in BHPrE1. These cell lines provide important data on progenitor and intermediate cell phenotypes and represent significant new tools for the elucidation of molecular mechanisms of human prostatic regeneration, pathogenesis, and carcinogenesis.
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PMID:Functional remodeling of benign human prostatic tissues in vivo by spontaneously immortalized progenitor and intermediate cells. 2002 Apr 26

The p53 gene super family consists of three members; TP53, TP63 and TP73, encoding proteins p53, p63 and p73. Whilst p63 appears to have an essential role in embryonic development with a less clear role in carcinogenesis, irregularities in p53 and p73 signalling are implicated in tumour formation. As such, p53 is a tumour suppressor which is mutated in over 50% cancers and p73 was recently formally classified as a tumour suppressor based on data showing p73 deficient mice generate spontaneous tumours similar to those observed in p53 null mice. Dysregulation of both p53 and p73 has been correlated with cancer progression in many cell types and although mutation of these genes is often observed, some form of p53/p73 deregulation likely occurs in all tumour cells. The discovery that complementary micro RNAs (miRNAs) are able to target both of these genes provides a potential new means of perturbing p53/p73 signalling networks in cancer cells. Here we summarise the current literature regarding the involvement of miRNAs in the modulation of p53 family proteins and cancer development and detail the use of in silico methods to reveal key miRNA targets.
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PMID:Regulating the genome surveillance system: miRNAs and the p53 super family. 2009 Dec 34

The cytosolic quinone oxidoreductases NQO1 and NQO2 protect cells against oxidative stress by detoxifying quinones and preventing redox cycling. In this study, we used double knockout (DKO) mice deficient for NQO1 and NQO2 to investigate the role of these antioxidative enzymes in a two-stage model of inflammatory skin carcinogenesis. In this model, tumors are caused by exposure to topical carcinogen dimethylbenz(a)anthracene or benzo(a)pyrene (BP) followed by twice weekly application of proinflammatory phorbol 12-myristate 13-acetate. On this classic chemical carcinogenesis protocol, DKO mice showed a significantly higher skin tumor frequency and multiplicity compared with control wild-type or single knockout mice. Analysis of skin from wild-type and DKO mice exposed to BP for 6, 12, or 24 hours revealed a relative delay in the activation of p53, p63, p19ARF, and apoptosis in DKO mice, consistent with a negative modifier role for NQO1/NQO2 in carcinogenesis. Our findings offer genetic evidence of the significance of quinone oxidoreductases NQO1 and NQO2 in limiting chemical skin carcinogenesis.
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PMID:Inactivation of the quinone oxidoreductases NQO1 and NQO2 strongly elevates the incidence and multiplicity of chemically induced skin tumors. 3038 11

TP63 gene is a member of TP53 tumor suppressor gene family that encodes several protein isoforms involved in the process of epithelial stratification and in epithelial-mesenchyme interactions. TP63 is amplified in a significant proportion of squamous cell carcinoma of the esophagus (ESCC), resulting in the hyper-expression of DeltaNp63 as the major p63 isoform. To better understand the contribution of this high expression to tumorigenesis, we have analyzed the impact of intraepithelial p63 expression on the expression of cell adhesion complexes in normal esophagus and in ESCC cell lines. Cells expressing p63 showed an adhesion pattern characterized by lack of tight junctions and presence of adherens junctions. Cell differentiation was accompanied by a decrease in p63 and by a shift to adhesion patterns involving tight junctions. Silencing of p63 mRNA in ESCC cell lines resulted in a similar shift, characterized by increased expression of component of tight junctions, decreased cell-to-cell communication and downregulation of cell proliferation. These results indicate that DeltaNp63 may contribute to esophageal squamous carcinogenesis by maintaining cell adhesion patterns compatible with cell proliferation.
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PMID:Intraepithelial p63-dependent expression of distinct components of cell adhesion complexes in normal esophageal mucosa and squamous cell carcinoma. 2012 60


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