Tumor Grade-Dependent Alterations in the Protein Kinase C Isoform Pattern in Urinary Bladder Carcinomas
Introduction
Protein kinase C (PKC) comprises a family of serine/threonine kinases that play central roles in the regulation of various cellular processes such as proliferation and tumorigenesis [1]. The members of the PKC family are the calcium- and phorbol ester-dependent “conventional” (cPKCα, βI, βII, and γ), the calcium-independent “novel” (nPKCδ, ε, η, and θ), the calcium- and phorbol ester-independent “atypical” (aPKCζ and λ/ι) isoforms and the unique PKCμ [2]. These isoforms possess a characteristic expression pattern in a given cell type, and regulate in an isoenzyme-specific, and very often antagonistic, fashion various cellular processes including cell growth, cell death and transformation [3]. For example, nPKCδ was suggested to promote cellular differentiation whereas, in contrast, PKCε of the same novel family was suggested as a key stimulator of in vitro and in vivo (tumor) growth of numerous cell types [3], [4].
Numerous reports have shown alterations in the PKC isoform pattern in parallel with the onset of cellular transformation leading to transformed phenotype in several tissues including e.g., fibroblasts [4], skin cells [5], [6], breast epithelium [7], uterus [8], and prostate [9], suggesting the role of the PKC system in the pathogenesis and progression of various tumors. However, up to date, only very few data have implicated the significance of the PKC system in the urinary bladder tumors [10], [11]. Therefore, in the current study, our goal was to define the possible alterations in the PKC isoform pattern of all three groups in relation with the different tumor grade in human urinary bladder carcinomas.
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Materials and methods
The study involved 23 cases (17 men, 6 women) of transitional cell carcinoma of the bladder removed by transurethral resection (17 cases), partial bladder resection (4 cases), or cystectomy (2 cases), and 6 samples of normal bladder obtained during prostatectomy. The removed samples were divided into two parts. One was processed to obtain formalin-fixed, paraffin-embedded sections and to perform routine haematoxylin-eosin staining-based grading [12] and staging according to the TNM system [13].
Results
Western blot analysis revealed that samples from both the normal and diseased urinary bladder epithelium expressed five PKC isoforms; the cPKCα and β, the nPKCδ and ε, and the aPKCζ (Fig. 1A). The other PKC isoforms (cPKCγ, nPKCη and θ, aPKCλ/ι, PKCμ) were not detected (data not shown). Of great importance, however, in the tumor samples of various grades we found marked yet differential alterations in the levels of the existing isoforms. As measured by quantitative densitometry analyses of the
Discussion
In this study we provide clear evidence that expressions of the existing five PKC isoforms differentially alter as a function of tumor grade of human urinary bladder carcinomas. Whereas the expressions of PKCβ and δ decreased with increasing grade of the tumors, the levels of PKCα, ε, and ζ showed opposite patterns of changes. These findings, similarly to numerous other tissues [3], [4], [5], [6], [7], [8], [9], strongly argue for a potential central role of the PKC system in the tumorigenesis
Acknowledgements
This work was supported by Hungarian research grants: OTKA F035036, OTKA T037531, OTKA TS040773, NKFP 00088/2001, OMFB 00200/2002, ETT 365/2003. Tamás Bı́ró is a recipient of the György Békésy Postdoctoral Scholarship.
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Attila Varga and Gabriella Czifra equally contributed to this work.