Expression of p14ARF, p15INK4b, p16INK4a, and DCR2 increases during prostate cancer progression

Abstract

Prostate carcinoma is a hormonally driven age-related neoplasm. Cellular senescence is an age-related process where cells remain metabolically active but in a growth-arrested state at the G1 phase. p14ARF, p15 INK4b, and p16INK4a, which are known to regulate G1 cell cycle arrest, and the tumor necrosis factor receptor superfamily member decoy receptor 2 (DCR2), have been recently identified as senescence markers. The purpose of this study was to characterize and compare the expression of p14 ARF, p15INK4b, p16INK4a, and DCR2 in tissue microarrays containing cases of normal prostate, nodular hyperplasia, prostate intraepithelial neoplasia (PIN), and malignant prostate cancer tissue. We performed immunohistochemical staining for p14ARF, p15 INK4b, p16INK4a, and DCR2 in tissue microarray blocks containing 41 cores of normal prostate, 65 cores of nodular hyperplasia, 21 cores of PIN, 69 cores of low-grade prostate carcinoma, and 42 cores of high-grade prostate carcinoma, derived from 80 cases of prostatectomy with adenocarcinomas. We detected positive staining of p16INK4a in 19% of the PIN, 25% of the low-grade carcinoma, and 43% of the high-grade carcinoma specimens but none in the normal prostate and nodular hyperplasia specimens. Expression of p14ARF revealed very high levels of expression in normal tissues (83%), nodular hyperplasia (88%), PIN (89%), and cancer cells (100%). P15INK4b and DCR2 were found positive in 81 and 33% normal, 46 and 10% nodular hyperplasia, 74 and 36% PIN tissues, 87 and 89% low-grade carcinomas, and 100 and 93% high-grade carcinomas. There is an increased protein expression of senescence-associated molecular markers, indicating that cellular senescence might play a role in prostate carcinoma. Because p16 INK4a-positive cells were detected only in premalignant lesions and carcinomas but not in normal or benign tissues, p16INK4a may aid in the diagnosis of PIN and prostate cancer in difficult cases. © 2006 USCAP, Inc. All rights reserved.