ABSTRACT
p53 is a tumour suppressor gene with an established role in the majority of human neoplasias. Its homologues-p63 and p73-cannot be classified as tumour suppressors, since they encode isoforms with oncogenic properties as well. p63 plays a crucial role in epithelial cell differentiation and p73 is essential for neuronal cell development. The p63 and p73 expressions have been investigated in a variety of human tumours including bladder carcinomas; yet, this is the first study to simultaneously analyse the transcriptional levels of all p53 family members in bladder cancer. Using quantitative real-time polymerase chain reaction, we measured the mRNA expression of p53, p63 and p73 in 30 bladder tumours, each paired with adjacent normal tissue. All three studied genes were up-regulated in malignant specimens, p53 by 1.9-fold, p63 by threefold and p73 by twofold, respectively. Further analysis suggested that p63 and p73 act independently of p53 in the malignant bladder epithelium. Statistical analysis revealed that p63 overexpression was more frequent in recurrent bladder tumours (p = 0.045) and in older patients (p = 0.022). Papillary tumours also exhibited abnormal p63 expression (p = 0.026). Finally, p73 was up-regulated in Grade III one-site tumours (p = 0.040). Our results indicate that all p53 family members are abnormally expressed in bladder cancer but do not act synergistically. High levels of p63 correlate with non-muscle invasive tumours with frequent relapses, whereas p73 overexpression is associated with a more aggressive tumour phenotype.
Subject(s)
DNA-Binding Proteins/biosynthesis , Membrane Proteins/biosynthesis , Neoplasm Recurrence, Local/genetics , Nuclear Proteins/biosynthesis , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Proteins/biosynthesis , Urinary Bladder Neoplasms/genetics , Aged , DNA-Binding Proteins/analysis , DNA-Binding Proteins/genetics , Female , Humans , Male , Membrane Proteins/analysis , Membrane Proteins/genetics , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Nuclear Proteins/analysis , Nuclear Proteins/genetics , Protein Isoforms/genetics , RNA, Messenger/analysis , Real-Time Polymerase Chain Reaction , Tumor Protein p73 , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/analysis , Tumor Suppressor Proteins/genetics , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathologyABSTRACT
The aim of the present study was to assess the possible etiologic role of human papillomavirus (HPV), human herpes virus (HHV) and the human polyoma virus families (BKV and JCV) in the tumourigenesis of bladder cancer. Thirty biopsy specimens from patients with different grades and stages of bladder cancer, who underwent transurethral bladder cancer resection, and 30 normal bladder mucosa specimens were analysed using polymerase chain reaction (PCR) for the detection of the above three virus family members. The presence of HPV was determined in all specimens with nested PCR and real-time quantitative PCR. All cancerous specimens, including the control group, were found to be negative both by PCR and real-time qPCR for the presence of HPV DNA, whilst all samples examined by PCR tested negative for the presence of HSV-1,2 Varicella zoster virus and HSV-7 DNA. Cytomegalovirus, HHV-6 and HHV-8 exhibited similar incidence in sample positivity in both cancerous and healthy tissues. EBV showed a higher prevalence in bladder cancer specimens compared to healthy tissue (p = 0.048), whilst BKV and JCV were detected only in tumour samples. The presence of EBV in a significant proportion of bladder tumours indicates the etiological role of this virus in cancer tumourigenesis.
Subject(s)
Herpesviridae/isolation & purification , Papillomaviridae/isolation & purification , Urinary Bladder Neoplasms/virology , Adult , Aged , Aged, 80 and over , Cell Transformation, Neoplastic , DNA, Viral/analysis , Female , Herpesviridae/genetics , Humans , Male , Middle Aged , Papillomaviridae/genetics , Polymerase Chain Reaction , Polyomavirus/genetics , Polyomavirus/isolation & purification , Real-Time Polymerase Chain ReactionABSTRACT
PURPOSE: p63 plays an important role in several intracellular processes such as transcription activation and apoptosis. p63 has two N-terminal isoforms, TAp63 and ΔNp63. TAp63 isoform has p53-like functions, while ΔNp63 acts as a dominant negative inhibitor of the p53 family and is considered oncogenic. Although p63 and its isoforms are overexpressed in a wide variety of human malignancies such as cervical, head and neck, and lung cancer, their role in endometrial carcinoma has not been investigated. METHODS: We measured by quantitative real-time polymerase chain reaction the mRNA expression of TAp63 and ΔNp63 in a series of 20 endometrioid adenocarcinomas paired with adjacent normal tissue. RESULTS: TAp63 isoform exhibited 1.8-fold overexpression in malignant samples, while ΔNp63 was 4.3-fold overexpressed in cancer specimens. Further analysis revealed that the ΔN/TA isoform ratio shifted from 0.5 in normal samples to 1.2 in tumor specimens. Statistical analysis also revealed an association of TAp63 expression with high body mass index (p = 0.034), late menopause (p = 0.020), and lower tumor grade (p = 0.034). ΔNp63 was also correlated with grade I/II tumors (p = 0.044). CONCLUSIONS: These results indicate that both p63 isoforms and especially ΔNp63 play an important role in the development and progression of grade I/II endometrial adenocarcinoma, especially in obese and late-menopause women.