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. p14 ARF , p15 INK4b , and p16 INK4a , 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 , p15 INK4b , p16 INK4a , 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 p14 ARF , p15 INK4b , p16 INK4a , 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 p16 INK4a 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 p14 ARF revealed very high levels of expression in normal tissues (83%), nodular hyperplasia (88%), PIN (89%), and cancer cells (100%). P15 INK4b 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, p16 INK4a may aid in the diagnosis of PIN and prostate cancer in difficult cases.

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

“…As has been suggested, OIS could have a role in the development of pre-malignant lesions, explaining p16 Ink4a overexpression in benign and pre-malignant lesions (Zhang et al, 2006;Campo-Trapero et al, 2008). However, p16 Ink4a should stop proliferation in cells with a properly functioning p16 Ink4a -Rb pathway.…”

“…Therefore, some benign tumors overexpress p16 Ink4a and this overexpression seems to control proliferation in response to oncogenic stimuli, protecting the cell from malignant transformation. This phenomenon could have a diagnostic application, as in the differential diagnosis from pre-malignant to malignant lesions in malignant peripheral nerve sheath tumor (unpublished data), melanoma (Hilliard et al, 2009) and prostate cancer, where p16 Ink4a immunopositivity has been described as a possible additional tool to differentiate between prostate intraepithelial neoplasia and carcinoma (Zhang et al, 2006). However, recent evidence suggests that not all kinds of cells have the ability to enter in senescence when faced with the same stimuli.…”

“…Several sources of evidence have suggested that the ability to bypass senescence is the main molecular mechanism involved in the progression of pre-malignant to malignant cells (Dai et al, 2000;Braig et al, 2005;Collado et al, 2005;Zhang et al, 2006). This hypothesis is based on the concept of oncogene-induced senescence, which was p16 Ink4a overexpression in cancer C Romagosa et al established after demonstration of p53-and p16 Ink4a -mediated senescent-like arrest in response to expression of oncogenic Ras in normal primary cells (Collado et al, 2007).…”

Molecular genetics of prostate cancer: new prospects for old challenges

“…Thus, SA-b-Gal, a commonly used biomarker of senescence, is frequently detected in BPH in the human prostate (Choi et al 2000;Castro et al 2003). Moreover, other markers of senescence, including p14 arf and p16 ink4a , are increased with aging and particularly in nonmalignant cancers, suggesting these may represent markers that distinguish indolent from more aggressive forms of the disease (Zhang et al 2006). In addition to senescence-related changes observed in epithelial cells, senescent primary prostatic fibroblasts display gene expression signatures associated with oxidative damage and DNA damage, which may in turn influence the invasive behavior of epithelial cells (Bavik et al 2006).…”

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

“…ARF derives from the INK4a/ARF locus in an alternative reading frame by alternate promoter usage and splicing that differs from the p16 cyclin-dependent kinase inhibitor that is more often mutated in cancer (17)(18)(19)(20)(21). Human p14-ARF shares only 50% homology with the p19-ARF mouse homologue (22), which indicates that the INK4a/ARF gene continued to evolve late within the mammalian lineage similar to the MAGE-A11 gene and AR NH 2 -terminal FXXLF motif flanking sequence required to interact with MAGE-A11.…”