Expression of p27 and its ubiquitin ligase subunit Skp2 in upper urinary tract transitional cell carcinoma.
OBJECTIVE
To analyze p27 and S-phase kinase-associated protein 2 (Skp2) expression in upper urinary tract transitional cell carcinoma (TCC) with respect to biologic significance. p27 (p27/kip1) is involved in cell cycle control, and loss of p27 protein expression may result in tumor development and/or progression. The association of p27 with the ubiquitin ligase subunit Skp2 targets p27 for degradation.


METHODS
A total of 53 upper urinary tract TCC specimens were investigated immunohistochemically using a tissue microarray technique. The immunoreactivity of p27 and Skp2 was analyzed with respect to associations with pT stage, grade, and prognosis.


RESULTS
Non-neoplastic renal tissue showed p27 immunoreactivity in tubule epithelium and pelvic urothelium, but lacked immunoreactivity for Skp2. In the TCC specimens, p27 immunoreactivity was noted in 47 (89%) of 53 cases. High p27 expression (50% or greater of tumor cell nuclei) tended to decrease with rising tumor stage (14 [45%] of 31 with pT1-pT2 versus 4 [18%] of 22 with pT3; P = 0.076), but was independent of tumor grade (11 [39%] of 28 grade 2 versus 7 [28%] of 25 grade 3-4; P = 0.56). Skp2 immunoreactivity was noted in 32 (60%) of 53 tumors. Skp2 expression increased with rising tumor stage (9 [41%] of 22 pT1 versus 23 [74%] of 31 pT2-pT3; P = 0.023) and tumor grade (12 [43%] of 28 grade 2 versus 20 [80%] of 25 grade 3; P = 0.043) and was associated with angioinvasion (P = 0.017). In multivariate analysis, tumor stage proved to be the only independent prognostic factor regarding disease-free survival.


CONCLUSIONS
p27 and Skp2 are additional biomarkers in urogenital pathologic findings. The statistically significant association of Skp2 expression with high-grade TCC, as well as the lack of expression in non-neoplastic tissue, suggests that Skp2 could be a promising target for future cancer therapy strategies.
Langner
Cord
C
Institute of Pathology, University of Graz Medical School, Graz, Austria.
von Wasielewski
Reinhard
R
Ratschek
Manfred
M
Rehak
Peter
P
Zigeuner
Richard
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002295:Carcinoma, Transitional Cell / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000032:analysis*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000737:chemistry; D007680:Kidney Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D009367:Neoplasm Staging; D011379:Prognosis; D044786:S-Phase Kinase-Associated Proteins / Q000032:analysis*; D016037:Single-Blind Method; D025521:Tumor Suppressor Proteins / Q000032:analysis*; D014516:Ureteral Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D019459:Urothelium / Q000737:chemistry
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27