Expression of Peroxisome Proliferator Activated Receptor gamma in Prostatic Adenocarcinoma

Autor: Hyunkyung Kim, Young Mee Cho, Hyung Kyu Park, Hye Seung Han, H. Kim, So Dug Lim, Woon Yong Jung, Tae Sook Hwang, Ghee Young Kwon
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: Journal of Korean Medical Science
ISSN: 1598-6357
1011-8934
Popis: Peroxisome proliferator-activated receptor gamma (PPAR-γ), a ligand-activated transcription factor has been investigated as the target for cancer treatment as well as metabolic disorders. Recent studies have demonstrated that PPAR-γ ligands are anti-tumorigenic in prostate cancer due to anti-proliferative and pro-differentiation effects. The aim of this study was to validate PPAR-γ expression in malignant and benign prostate tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). A total of 730 prostatic adenocarcinomas (PCAs) including 63 whole sections from radical prostatectomy specimens and tissue microarrays containing 667 PCAs were subject to immunostaining for two PPAR-γ antibodies. Twenty-five benign prostate tissues and PCAs were selected for investigating mRNA expression by quantitative real-time PCR. 10.7% of PCAs (78/730) showed cytoplasmic immunoreactivity of PPAR-γ and no nuclear immunoreactivity was noted in PCAs. Most benign prostatic glands showed negative immunoreactivity of PPAR-γ except for variable weak cytoplasmic staining in some glands. Nuclear immunoreactivity of PPAR-γ was noted some central zone and verumontanum mucosal epithelium. The constitutive PPAR-γ mRNA showed significantly lower level in PCAs compared to that in the benign tissues. There was no difference of PPAR-γ mRNA expression between low (≤7) and high (>7) Gleason score groups. There was no association of PPAR-γ mRNA level or cytoplasmic immunostaining with Gleason grade or pathologic stage. Our study supported the evidence of extra-nuclear localization and nongenomic actions of PPAR-γ. Further studies are needed to assess the functional role of PPAR-γ and to validate its therapeutic implication in prostate cancer. Graphical Abstract Keywords: Prostatic Neoplasms, PPAR gamma, Immunohistochemistry, Real-Time Polymerase Chain Reaction INTRODUCTION Prostate cancer is the second most frequently diagnosed cancer affecting male adults and the sixth most common cause of cancer associated death in men across the world (1). The major risk factors for prostate cancer are old age, race, inherited susceptibility and environmental and behavioral factors such as diets (2, 3). Treatment options of prostate cancer include active surveillance, surgical resection, androgen ablation therapy, radiotherapy, and cryotherapy variously depending on risk grouping, medical comorbidities and age at the diagnosis of the patients (4, 5, 6). Prostate cancer is heterogeneous in terms of clinical behaviors, histological and molecular features, and treatment options (4, 5, 6, 7). Although most patients with low and intermediate-risk prostate cancer follow an indolent clinical course and are potentially curative by surgical resection or radiotherapy, patients with high-risk prostate cancer have higher rate of cancer related death and conventional chemotherapy and radiation therapy are of limited effectiveness for them (2, 4, 5, 6, 8). Androgen deprivation therapy has good efficacy for advanced disease to lead to either a partial or complete remission initially. However most patients evolve towards an androgen-independent state within a few years and result in death due to widespread metastasis (6). Therefore, more improved treatments and novel biomarkers are strongly needed in order to overcome metastasis and lethal recurrence for advanced prostate cancer as well as unpredictable cases of low or intermediate risk groups. Peroxisome proliferator-activated receptors (PPARs) are a group of 50-kDa ligand-dependent transcription factors localized at human chromosome 3p25 and belong to a member of the nuclear hormone receptor superfamily such as steroid and thyroid hormones (9, 10, 11). They are composed of three isoforms (PPAR-α, PPAR-γ, and PPAR-δ/β) and require heterodimerization with the retinoid X receptor for optimal DNA binding to specific response elements, termed to as peroxisome proliferator response elements (PPREs), in the promoter of the various target genes (9, 10, 11). The nuclear receptor superfamily was named because they show prominent nuclear localization. Among the subtypes, PPAR-γ is known to play a prominent role in adipocyte differentiation, the inflammatory response and peripheral glucose utilization (9, 11). Recent studies have suggested that PPAR-γ play a key role in tumorigenesis as a tumor suppressor and PPAR-γ agonists showed antiproliferative and proapoptotic actions in cancers (8, 12, 13). Currently PPAR-γ agonists including the most active natural ligand, 15-deoxy-D-12, 14-prostaglandin J2 (15-dPGJ2) and the most specific PPAR-γ synthetic agonists, the thiazolidinediones (TZDs) are used for enhancing insulin sensitivity in type II diabetes patients (9). And they have been introduced in clinical trials for treatment of several malignancies such as colorectal and esophageal cancers (9, 14). Many in vivo or in vitro studies have shown antineoplastic effect of PPAR-γ ligands in prostate cancers (15, 16). It has been reported that exposure to the TZDs has been shown to increase apoptotic activity in LNCaP, C4-2, and PC-3 prostate cancer cells and a combination therapy using histone deacetylases inhibitors and PPAR-γ agonists decrease invasiveness of the prostate adenocarcinoma cells in vivo (13, 15, 16). Efatutazone is recently introduced as a novel third-generation TZD PPAR-γ agonist, which is at least 500-fold more potent than the other TZDs such as troglitazone and pioglitazone (17). Therefore, PPAR-γ and its agonists have recently drawn more attention and promise in terms of chemoprevention and chemotherapy for cancer treatment and it has been also considered as a promising molecular target for anticancer targeted therapy development in prostate cancers (18). However, there is little or controversial information on PPAR-γ expression and clinical implications in the clinical specimen of prostate cancers (18, 19, 20). Whereas Nakamura et al. (19) reported PPAR-γ expression showed an inverse correlation with worse clinical parameters including pT stage and serum PSA levels, Rogenhofer et al. (20) reported PPAR-γ protein and mRNA expression were found to be significantly higher in advanced prostate cancers than in localized cancer. Therefore, further studies are needed to obtain a better understanding of the clinical roles of PPAR-γ in human prostate cancers for considering a potential trial of PPAR-γ ligands therapy for the patients. The aim of this study was to validate PPAR-γ expression in malignant and benign prostate tissues of a clinically well-characterized prostatectomy cohort by immunohistochemistry and quantitative real-time PCR in a Korean population.
Databáze: OpenAIRE
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