Loss of nuclear p27(kip1) and α-dystroglycan is a frequent event and is a strong predictor of poor outcome in renal cell carcinoma.
Expression levels of p27(kip1) , a negative regulator of the G1 phase of the cell cycle, and 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, were assessed by immunostaining in a series of renal cell carcinomas (RCCs) and their prognostic significance was evaluated. Expression of p27(kip1) as well as of the α-subunit of the dystroglycan (DG) complex, previously reported to be altered in RCC, was also evaluated by western blot analysis. Nuclear expression of p27(kip1) was reduced in a significant fraction of tumors and low p27(kip1) staining correlated with higher tumor grade (P < 0.01). Recurrence and death from clear cell RCCs were significantly more frequent in p27(kip1) -low expressing tumors and Kaplan-Meier curves showed a significant separation between high vs low expressor groups for both disease-free (P = 0.011) and overall (P = 0.002) survival. Low nuclear expression of p27(kip1) as well as loss of α-DG were confirmed to be independent prognostic parameters at a multivariate analysis and the simultaneous loss of both molecules defined a "high-risk" group of patients with increased risk of recurrence (RR = 28.7; P = 0.01) and death (RR = 12.9; P = 0.03). No significant correlation with clinical or pathological parameters was found for 8-OHdG staining. Western blot analyses suggested a post-translational mechanism for the loss of α-DG expression and demonstrated that cytoplasmic dislocation of the protein contributes to the loss of active nuclear p27(kip1) . Loss of nuclear p27(kip1) is a frequent event in human RCCs and is a powerful predictor of poor outcome which, in combination with low DG expression, could help to identify high-risk patients with clear cell RCC.
Sgambato
Alessandro
A
"Giovanni XXIII" Cancer Research Center - Institute of General Pathology, Catholic University, Rome, Italy. asgambato@rm.unicatt.it
Camerini
Andrea
A
Genovese
Giannicola
G
De Luca
Filomena
F
Viacava
Paolo
P
Migaldi
Mario
M
Boninsegna
Alma
A
Cecchi
Massimo
M
Sepich
Carlo A
CA
Rossi
Giulio
G
Arena
Vincenzo
V
Cittadini
Achille
A
Amoroso
Domenico
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D049030:Dystroglycans / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017063:Outcome Assessment, Health Care; D011237:Predictive Value of Tests; D011379:Prognosis; D055815:Young Adult
D049030:Dystroglycans; D050760:Cyclin-Dependent Kinase Inhibitor p27