Frequent alteration of p63 expression in human primary bladder carcinomas

p63, a recently identified member of the p53 gene family, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. To explore the penetrance of p63 in bladder carcinogenesis, we performed expression and mutation analyses of two major isotypes, TAp63 and deltaNp63, in 63 bladder specimens. In 12 normal tissues, TAp63 was expressed at an easily detectable level whereas deltaNp63 was absent or extremely low. While none of 47 carcinomas showed allelic deletion of the gene, marked reduction of TAp63 and abnormal overexpression of deltaNp63 were found in 25 (53.2%) and 30 (63.8%) carcinomas, respectively. Tumor-specific alteration of TAp63 and deltaNp63 expression was identified in two and three of six matched sets, respectively. In addition, reduced expression of TAp63 showed a correlation with tumor stage and grade. Abnormal expression of TAp63 or deltaNp63 isoform was also observed in three of four cell lines, and treatment with 5-Aza-2'-deoxycytidine led to up- or down-regulation of TAp63 and/or deltaNp63 expression, suggesting that the promoters of both isoforms might be affected by DNA methylation, but not in a reciprocal fashion. No sequence alteration of p63 was identified in 47 carcinomas whereas 17 (34.8%) of these showed p53 mutations, and no association between p63 expression and the mutational status of p53 or expression of p21Waf1, MDM2, and 14-3-3sigma was recognized. Our data suggest that altered expression of p63 is a frequent event in bladder carcinogenesis and might contribute to the progression of bladder tumors, possibly via the mechanism(s) distinct from the p53 pathway.     

Expression of p53 and its homologues in primary and recurrent squamous cell carcinomas of the head and neck

The tumour-suppressor protein p53 belongs to a family that includes 2 structurally related proteins, p63 and p73. Because of their structural homology, it has been hypothesized that both homologues serve as "spare mechanisms" in p53 mutations to regulate the cell cycle by inducing apoptosis. We investigated the mutational and protein expression status of p53 in correlation to its homologues, p73 and p63, in primary and recurrent squamous cell carcinomas of the head and neck (HNSCC) and corresponding nonneoplastic mucosa. Expression and mutation of p53 and its homologues p63 (including the 2 major isotypes TAp63 and DeltaNp63) and p73 was examined by direct DNA sequencing and immunohistochemistry in 29 primary and 39 recurrent (secondary) HNSCCs after microdissection. Our results were correlated with pathohistologic stage and grade. p53 mutations were detected in 32/68 (47%) carcinomas of 17 patients, with a discordant mutation pattern of primary and consecutive tumours in all cases. Positive immunostaining for p63 was found in 55/68 (81%) carcinomas of 29 patients. Immunohistochemistry revealed p73 protein expression in 32/68 (47%) tumours. In normal mucosa, p63 and p73 were expressed in 40/68 (59%) and 12/68 (18%) cases, respectively. We failed to detect specific mutations of p73 or p63 in primary and recurrent carcinoma of the head and neck. p73 and p63 were rarely mutated in HNSCC, but both were expressed in a subset of tumours. The lack of correlation between p73/p63 and p53 protein expression suggests that neither p73 nor p63 can replace p53 when it is mutated.     

DeltaNp63 expression is associated with poor survival in ovarian cancer.

BACKGROUND: P63 belongs to the 'p53 family' whose role in cancer progression has been recently revisited in light of the plethora of splicing variants that are generated. We analyzed the expression of the full-length TAp63 gene and its dominant-negative form deltaNp63 in ovarian cancer biopsies to correlate their expression with clinical outcome. MATERIALS AND METHODS: Real-time RT-PCR analysis was used to determine the levels of TAp63 and deltaNp63 in 83 stage I and in 86 stage III ovarian cancer biopsies and in seven human ovarian cancer cell. RESULTS: TAp63 levels were comparable in stage I and stage III, but deltaNp63 levels increased 77-fold in stage III, independently of the p53 status. Patients with high deltaNp63 expression had the worst overall survival (OS); patients with a deltaNp63/TAp63 ratio >2 had a poor OS. Patients with a high deltaNp63/TAp63 ratio were those with a poor response to platinum-based therapy. CONCLUSIONS: Data indicate a role for deltaNp63 as a potential biomarker to predict patient's outcome and tumor progression in ovarian cancer. This would have particularly clinical relevance in ovarian cancer where the high rate of mortality reflects our lack of knowledge of molecular mechanisms underlying cell progression toward malignancy.     

p63 expression is associated with p53 loss in oral-esophageal epithelia of p53-deficient mice

The p53 gene family, comprising p53, p63, and p73, has overlapping and distinctive functional roles. These members share structural similarities allowing for dynamic interplay in the activation of genes that are important in development and key cellular functions, such as the induction of apoptosis. Whereas p53 is a classical tumor suppressor gene, p63 and p73 do not share this feature in cancer formation and progression. The compensation in the expression level of these members in a background that is deficient for one of them has not been examined previously. Given the importance of p63 in the development and differentiation of oral-esophageal stratified squamous epithelia and the absence of oral-esophageal tumors in p53-null mice, we postulated and describe herein that p63 expression is associated with the loss of p53 in a p53-deficient background. Both full-length and amino-truncated forms of p63 are expressed and increased in oral-esophageal epithelia of p53-null mice when compared with wild-type mice, and the induction of p21 may potentially be preserved through the increase of p63.     

Transcriptional dysregulation of the p73L / p63 / p51 / p40 / KET gene in human squamous cell carcinomas: expression of Delta Np73L, a novel dominant-negative isoform, and loss of expression of the potential tumour suppressor p51

We have recently identified a second p53 -related p73L gene, also referred to as p63 / p51 / p40 / KET gene, which encodes the 2 major isoforms p73L and p51 resulting from different exon usage at their amino terminal regions. Although p73L and p51 are suspected to play oncogenic and tumour suppressive roles in mammalian cells, respectively, no evidence of linkage between the expression of these isoforms and human cancers has been reported so far. In this study, we first investigated the expression profile of p51 and p73L in various human tumour cell lines and found that a novel isoform, termed DeltaNp73L, was predominantly expressed in squamous cell carcinomas. The expression profile of DeltaNp73L/p73L/p51 in primary human skin cancer specimens showed that the expression of p51 was frequently lost (62%) but was detected in all normal skin samples. In p51-expressing skin cancers, DeltaNp73L expression was associated at a high frequency (75%) though it was not detected in normal skin tissues. Transient co-transfection data indicate the possibility that DeltaNp73L can inhibit p53-, and more preferentially, p51-mediated transactivation. These data suggest that the loss of expression of p51 and/or the expression of DeltaNp73L might contribute to the pathogenesis of human squamous cell carcinomas.     

p53基因家族的新成员 p73和 p63

p53作为广泛存在的肿瘤抑制基因,最近发现了其家族成员：p73和p63。它们在结构和功能上具有相似性,均能触发细胞周期停滞,诱导凋亡,但它们在肿瘤抑制和组织发育中起着截然不同的作用,深入了解它们彼此之间的相似性和差异将对理解肿瘤发生的机制产生重要的影响。本文总结了最近几年来此领域内的最新进展。另外,p73和p63在C端的SAM结构说明它们可能参与组织的发育过程。     

Clinicopathologic significance of an immunohistochemical expression of p27 in scirrhous carcinoma of the breast

BACKGROUND: Scirrhous carcinoma has been known to have more aggressive biological behavior than other histologic subtypes of invasive ductal carcinoma of the breast. The significance of expression of p27kip1, which is thought to be a tumor suppressor gene, in breast carcinoma remains controversial. The aim of the current study was to clarify clinicopathologic significance of scirrhous carcinoma of the breast with special reference to p27 expression. METHODS: Clinicopathologic features including immunohistochemical expression of p27 were compared between scirrhous carcinoma (n=42) and non-scirrhous invasive ductal carcinoma (papillotubular and solid-tubular carcinoma, n=63) of the breast. RESULTS: The proportion of pathologic lymph node metastasis among scirrhous carcinomas was significantly higher than that among carcinomas of other histologic types (papillotubular or solid-tubular carcinomas, p=0.029). The proportion of strong expression of p27 among scirrhous carcinomas was significantly lower than that among tumors of other histologic types (p<0.0001). CONCLUSIONS: Biological behavior of scirrhous carcinoma was found to be aggressive. The aggressiveness and poor cellular differentiation of scirrhous carcinoma of the breast might be related to low p27 expression.     

p63: defining roles in morphogenesis, homeostasis, and neoplasia of the epidermis

p63 is a member of a gene family also including the p53 tumor suppressor and p73. In contrast to p53, p63 is rarely mutated in human cancers. Rather, gene amplification and dysregulated expression of p63 protein have been observed, particularly in squamous cell carcinomas. p63 is essential for development of stratified squamous epithelium, including the epidermis. The p63 gene is expressed as multiple protein isoforms with different functional capacities, and the balance of these isoforms, along with the presence or absence of the other family members, p53 and p73, can impact biological outcome. Both gene silencing and overexpression approaches have been utilized to elucidate the contributions of specific p63 isoforms to normal epidermal morphogenesis and tissue maintenance. While numerous studies have established the essential nature of p63 in the epidermis, the basis of this requirement, and the unique, as well as, overlapping functions of the individual isoforms, remain controversial. In this review, we summarize the current understanding of roles played by specific p63 isoforms within the context of epidermal morphogenesis and homeostasis of the established epidermis, and the potential impact of p63 dysregulation on cancer development.     

Overexpressions of Ha-ras and p53 predict the prognosis of patients with non-small-cell lung carcinoma

Activationofprotooncogenesandinactivationoftumor-suppressorgeneshavebeenshowntoplayanimportantroleincarcinogenesis.Inhumantumors,alterationsoftherasprotooncogenesandp53tumor-suppressorgenehavebeenwidelyinvestigated[1-6].Thethreemembersoftherasprotooncogenefamily,Ki-ras,Ha-ras,andN-ras,encodep2l(ras)[ras][1,2].Pointmutationsoftherasprotooncogenes,resultinginmutatedformsofrasp21,andanenhancedexpressionofthenormalcellularrasp2laretwomechanismsknowntoleadtoactivationoftherasprotooncogenefamily[7,…