However, there is possibility of contamination from other bladder or urethral sites, beside the tumor tissue, when using bladder wash samples in this study. Thus, further studies need to evaluate the relationship between HPV prevalence and pathological grade. Conversely, the pathological grade differed according to the material settings

in which the target samples were primary or recurrent. Furthermore, the number of samples has been limited as above, Selleck SB431542 and further studies are required to reach a more definite conclusion. The pathological grade generally has a potential effect on the recuperation of the patients with bladder carcinoma. Thus, it is an interesting issue on the effect of HPV infection in the prognosis of patients with bladder carcinoma. In the carcinogenic process of low-grade non-invasive bladder cancer or high-grade invasive bladder cancer, two different biological pathways have been proposed. One pathway for low-grade cancer is involved in chromosome 9 allelic loss and higher p16 expression,

whereas another pathway for high-grade invasive cancer is characterized by p53 mutation and lack of p16, Ras, or fibroblast growth factor receptor-3 (FGFR3) expression [79]. HPV-E6 protein and E7 are well known as oncogenic proteins. HPV-E6 contributes to the loss of function of p53, one of the main cancer-suppression genes, by ubiquitination of this gene and enhancement Y-27632 mouse of proteasome activity. In addition, E6 protein also suppresses the transcription of p53 directly. As described above, some previous studies described the relationships between HPV infection and p53 expression in bladder carcinoma. Tenti et al. indicated that HPV was more frequently detected in low-grade tumors than in high-grade tumors in which mutations of p53 protein were commonly observed [44]. However, Moonen et al. found no correlation between HPV infection and p53 overexpression in high-grade tumors [65]. Kamel et al. also reported that no correlations between HPV positivity and p53 protein

accumulation were observed in bladder carcinoma [37]. As other events related ADP ribosylation factor to the p53 gene are commonly observed in bladder carcinoma regardless of HPV detection, no definite conclusions on the relationship between p53 expression and HPV infection can be reached. Moreover, it is well known that another oncogenic protein, HPV-E7, inactivates pRb, resulting in commencement of cell proliferation. P16-INK4a is the cancer suppression gene that suppresses inactivation of the Rb protein, and the loss or mutation of p16 expression is often a critical event in the progression of many carcinomas, including bladder carcinoma [80]. However, high levels of p16-INK4a expression are linked to HPV-E7 activity, and these molecules are strongly expressed in high-grade cervical intraepithelial neoplasia and cervical cancer.