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. 2002 Oct;161(4):1199-206.
doi: 10.1016/S0002-9440(10)64396-9.

Loss of p63 expression is associated with tumor progression in bladder cancer

Marshall J Urist  1 , Charles J Di Como, Ming-Lan Lu, Elizabeth Charytonowicz, David Verbel, Christopher P Crum, Tan A Ince, Frank D McKeon, Carlos Cordon-Cardo
Affiliations

Loss of p63 expression is associated with tumor progression in bladder cancer

Marshall J Urist (VSports手机版) et al. Am J Pathol. 2002 Oct.

Abstract

p63, a member of the p53 gene family, encodes multiple proteins that may either transactivate p53 responsive genes (TAp63) or act as a dominant-negative factor toward p53 and p73 (Delta Np63). p63 is expressed in many epithelial compartments and p63(-/-) mice fail to develop skin, prostate, and mammary glands among other defects. It has been previously shown that p63 is expressed in normal urothelium VSports手机版. This study reports that p63 is regulated in bladder carcinogenesis and that p63 expression is lost in most invasive cancers whereas papillary superficial tumors maintain p63 expression. Examination of bladder carcinoma cell lines reveals that certain lines derived from invasive carcinomas maintain expression of Delta Np63, as demonstrated by both immunoblotting and confirmed by isoform-specific quantitative reverse transcriptase-polymerase chain reaction. Another novel finding reported in this study is the fact that p63(-/-) mice develop a bladder mucosa epithelial layer yet fail to complete uroepithelial differentiation, producing a nontransitional default cuboidal epithelium. These data indicate that in contrast to the skin and prostate, p63 is not required for formation of a bladder epithelium but is indispensable for the specific differentiation of a transitional urothelium. .

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Figures

Figure 1.
Figure 1.
Representative photomicrographs of immunophenotypes of p63 in normal human urothelium and TCC using the anti-p63 4A4 monoclonal antibody. Normal urothelium (A); low-grade superficial TCC (B); invasive TCC (C, D). Arrayed tissues are formalin-fixed and paraffin-embedded. DAB was used as the chromogen and hematoxylin as the nuclear counterstain. Original magnifications: ×400 (A); ×200 (B–D).
Figure 2.
Figure 2.
Analysis of p63 RNA and protein expression in human TCC cell lines. A: Western blot analysis in which 100 μg of total cell extract was loaded onto 10% SDS-PAGE, followed by Western blotting using the mouse anti-human p63 monoclonal antibody 4A4 and the mouse anti-human Ran monoclonal antibody as a loading control. B: Western blot analysis in which 30 μg of H1299 total cell extract was loaded onto 12% SDS-PAGE, followed by Western blotting using the mouse anti-myc monoclonal antibody 9E10 (to detect the transfected myc-tagged p63 isoforms) and the mouse anti-human actin monoclonal antibody AC-40 as a loading control. For both A and B, horseradish peroxidase-conjugated rabbit anti-mouse IgG was used as the secondary antibody, followed by enhanced chemiluminescence.
Figure 3.
Figure 3.
RT-PCR for p63 isoforms in TCC cell lines. Quantitative RT-PCR analyses of ΔNp63 in which 100 ng of total RNA template, 1.25 U of 40× Multiscribe enzyme mix, probe (final concentration, 100 nmol/L), and ΔNp63 primers (final concentration, 50 nmol/L) were added in a 50 μl reaction volume. The y axis represents equivalent nanograms of HaCaT total RNA normalized to the endogenous control glyceraldehyde-3-phosphate (GAPDH) in each sample. All samples were amplified in triplicate.
Figure 4.
Figure 4.
Analysis of bladder development in p63−/− mice. Cystic (A) and ureteric (C) transitional epithelium of p63+/+ mice. Arrows indicate terminally differentiated umbrella cells. Cystic (B) and ureteric (D) transitional epithelium of p63−/− mice. Note lack of umbrella cells. Formalin-fixed and paraffin-embedded mouse embryos were sectioned and stained with H&E.
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References

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