Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To date, several reports have been published about CpG island methylation of various genes in prostate cancer. However, most of these studies have focused on cancer tissue only or a single gene and data about concurrent methylation of multiple genes in prostate cancer or prostatic intraepithelial neoplasia (PIN) are limited. The aim of the present study was to determine the methylation profile of 11 tumour-related genes in prostate cancer and PIN. Seventy-one samples, including 37 prostate cancers, 14 PINs, and 20 normal prostates, were examined for the methylation status of 11 tumour-related genes using methylation-specific PCR. The mean number of genes methylated was significantly higher in prostate cancer and PIN than in non-neoplastic prostate (4.4, 3, and 0.2, respectively; p < 0.001). In prostate cancer, APC, GSTP1, MGMT, and RASSF1A were frequently methylated at a frequency of 56.8%, 86.5%, 75.7%, and 83.8%, respectively. These genes were methylated in more than 30% of PINs. Prostate cancers with high serum prostate-specific antigen (PSA) (more than 8 ng/ml) or a high Gleason score (GS) (3 + 4 or more) showed higher numbers of methylated genes than those with low serum PSA (8 or less) or low GS (3 + 3 or less) (5.4 versus 2.5 and 5.4 versus 3.1, respectively; p < 0.05). The methylation frequency of APC, RASSF1A, and RUNX3 was higher in prostate cancers with high serum PSA or with high GS than in those with low PSA or with low GS, respectively, the differences reaching statistical significance (p < 0.05). A strong association between MGMT methylation and loss of MGMT expression was demonstrated by immunohistochemistry. CpG island methylation is a frequent event, occurs early, and accumulates during multi-step prostatic carcinogenesis. High levels of CpG island hypermethylation might serve as a potential biological marker for aggressive prostate cancer.
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PMID:Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia. 1474 6

Androgens play a critical role in regulating the growth, differentiation and survival of epithelial cells in many androgen-responsive organs, such as prostate and skin. The enzyme steroid 5alpha-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone (T) to a more active androgen, dihydrotestosterone (DHT). DHT then binds to androgen receptors (AR) and functions in the nucleus to regulate specific gene expression. Androgens via their cognate receptor may be involved in the development and progression of benign prostate hyperplasia, prostate cancer, hirsutism, male pattern alopecia and acne. The aim of this study was to determine whether theaflavin-3,3'-digallate (TF3) and penta-O-galloyl-beta-D-glucose (5GG) have inhibitory effects on androgen production and action. We found that TF3 and 5GG inhibit rat liver microsomal 5alpha-reductase activity. Furthermore, TF3 and 5GG significantly reduced androgen-responsive LNCaP prostate cancer cell growth, suppressed expression of the AR and lowered androgen-induced prostate-specific antigen secretion and fatty acid synthase protein level. In conclusion, our result suggests that TF3 and 5GG might be useful chemoprevention agents for prostate cancer through suppressing the function of androgen and its receptor.
Carcinogenesis 2004 Jul
PMID:Theaflavin-3,3'-digallate and penta-O-galloyl-beta-D-glucose inhibit rat liver microsomal 5alpha-reductase activity and the expression of androgen receptor in LNCaP prostate cancer cells. 1496 12

Beta-catenin in its role as a nuclear signaling molecule has been implicated in prostate carcinogenesis primarily through modulation of androgen receptor activity. We defined the pattern of beta-catenin protein expression in the nuclei of normal, hyperplastic and malignant human prostate tissue and determined whether differences in expression were associated with disease progression and prognosis. Five normal prostates, 26 benign prostatic hypertrophy specimens, 232 radical prostatectomy specimens from patients with clinically localized prostate cancer (PC) and 20 cases of advanced PC were assessed for beta-catenin expression using immunohistochemistry. Nuclear beta-catenin expression in localized PC was significantly lower than that in benign prostate tissue (p < 0.001) and significantly higher than that in advanced PC tissue (p < 0.001). In addition, lower levels of nuclear beta-catenin expression (< 10% of cancer cells) predicted for a shorter biochemical relapse-free survival in patients with localized PC (p = 0.008) and were inversely correlated with preoperative prostate-specific antigen (PSA) levels (p = 0.01). Analysis of the low-risk subgroup of patients with preoperative PSA levels < 10 ng/ml demonstrated that lower levels of nuclear beta-catenin expression (< 10% of cancer cells) again predicted for a poorer prognosis (p = 0.006). In conclusion, lower levels of nuclear beta-catenin expression are found in malignant compared to benign prostate tissue. In addition, lower nuclear beta-catenin expression is associated with a poorer prognosis in localized PC, in particular, in the low-risk subgroup of patients with preoperative PSA levels < 10 ng/ml. Thus, the level of nuclear beta-catenin expression may be of clinical utility as a preoperative prognostic marker in low-risk localized PC.
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PMID:Lower levels of nuclear beta-catenin predict for a poorer prognosis in localized prostate cancer. 1545 87

Early diagnosis of prostate cancer holds tremendous promise for the effective therapy and impact on survival of prostate cancer patients. High-grade prostatic intraepithelial neoplasia (HGPIN) is generally accepted as a lesion indicative of a late pathological event in the premalignant changes leading to full development of prostate cancer. This review seeks to identify specific molecular events that may be linked directly to the molecular transition from benign prostate epithelial cells to prostate carcinoma. HGPIN is pathologically detected in a limited group of men undergoing prostate cancer screening for an elevated serum prostate-specific antigen (PSA) or abnormal digital rectal examination (DRE). Loss of apoptotic control provides a molecular basis for the contribution of specific defective steps in the pathway towards development and progression of prostate cancer. Comparative dissection of the apoptosis status and expression profile of key apoptotic regulators among foci of highly proliferative benign prostatic epithelium, PIN and prostate adenocarcinoma from adjacent areas of the same gland revealed a novel insight into the dysfunctional apoptosis events contributing to prostate carcinogenesis. The sequential and notable loss of the three critical signaling components of the apoptotic action of transforming growth factor-beta (TGF-beta), in the prostate, that is, the transmembrane receptor II (TbetaRII), the key cell cycle inhibitor p27(Kip1), as well as the protagonist downstream effector of the TGF-beta signaling mechanism, Smad4, points to their potential value to 'faithfully' characterize HGPIN, as a premalignant prostate lesion. Recent evidence on the molecular changes in apoptosis regulators contributing to HGPIN and their role as molecular markers of disease onset, as well as candidates for therapeutic targeting/chemoprevention of prostate cancer in its early stages will be discussed.
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PMID:Apoptotic regulators in prostatic intraepithelial neoplasia (PIN): value in prostate cancer detection and prevention. 1547 76

The formation of DNA adducts can lead to DNA replication errors and the potential for carcinogenesis. DNA adducts have been detected in prostate cells, but the distribution of adducts with respect to prostate cancer risk factors and histology is unknown. In a study of 130 Caucasian (n = 61) and African-American (n = 69) men with prostate cancer who underwent radical prostatectomy, we quantified polycyclic aromatic hydrocarbon (PAH)-DNA adducts in prostate tumor and adjacent nontumor cells by immunohistochemistry. A strong correlation between paired adduct levels in the two cell types was observed (r = 0.56; P < 0.0001); however, nontumor cells had a significantly higher level of adducts compared with tumor (0.30 absorbance units +/- 0.05 versus 0.17 absorbance units +/- 0.04; P < 0.0001). Variables significantly associated with PAH-DNA adduct levels in tumor cells included primary Gleason grade, tumor volume, and log-transformed prostate-specific antigen (PSA) at time of diagnosis. Tumors with a primary Gleason grade of 5 had significantly lower PAH-DNA adduct levels than tumor cells with a primary Gleason grade of 3 or 4 (P < 0.0001 for both). Tumors that involved 10% or less of the prostate gland had significantly higher PAH-DNA adduct levels than tumors that involved 15 to 20% of the prostate gland (P = 0.004). PSA levels were inversely associated with PAH-DNA adduct levels in tumor cells (P = 0.009). A similar, albeit less significant, inverse association was observed between PSA and PAH-DNA adduct levels in nontumor cells (P = 0.07). Interestingly, increasing primary Gleason grade was associated with increasing PAH-DNA adduct levels in adjacent nontumor cells (P = 0.008). Our results show that PAH-DNA adducts are present in the prostate but vary with regard to cellular histology. In prostate tumor cells, decreased cellular differentiation and increased tumor proliferation may reduce PAH-DNA adduct levels.
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PMID:Polycyclic aromatic hydrocarbon-DNA adducts in prostate cancer. 1560 44

Androgens are known to play an important role in normal prostate development, benign prostatic hyperplasia, established prostate cancer, and in prostate carcinogenesis. However, despite convincing experimental and clinical evidence, the epidemiologic data correlating sex steroid levels with disease risk is inconsistent. More recent work has focused on studies of polymorphisms in germ-line DNA in an effort to develop polygenic models of prostate cancer susceptibility and prognosis. Such models have the potential to aid in the selection of men for specific chemopreventive interventions and to help determine which men with localized prostate cancer are most likely to benefit from aggressive therapy. In this review, we will provide a brief summary of androgen metabolic pathways followed by an assessment of the epidemiology literature addressing the relationship between androgens and prostate cancer. Finally, we will address the two major questions that have arisen in response to the recently published results from the Prostate Cancer Prevention Trial: Who are the best candidates for finasteride chemoprevention, and what are the clinical implications of the high prevalence of prostate cancer that was detected in men with prostate-specific antigen levels in the so-called "normal" range?
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PMID:Prevention of hormone-related cancers: prostate cancer. 1563 99

The transactivation function of the human androgen receptor (AR) can be regulated by several coregulators that may be either positive or negative. Ubiquitous transcription factor Sp1 not only regulates the basal expression of the AR but also acts as its coregulator. Our previous study has shown that quercetin, one of the main polyphenols, can effectively inhibit the expression and function of the AR. The present study is to address if quercetin may affect Sp1's action on AR transactivation activity in human prostate adenocarcinoma cell lines, LNCaP and PC-3. First, we showed that indeed in transient transfections Sp1 could enhance transcriptional activity of the AR promoter and of androgen upregulated gene promoters, i.e. the prostate-specific antigen and the hK2 genes. Interestingly, the enhancing activity of Sp1 could be repressed by quercetin. The gel shift and western blot analyses indicated that the specific DNA motif binding activity of Sp1 and its protein levels were not altered by quercetin. However, the state of interaction of Sp1 with the AR treated by quercetin plus androgen was different from that by androgen treatment or none as demonstrated by coimmunoprecipitation experiments and glutathione S-transferase (GST) pull-down assays. Moreover, we showed that quercetin caused changes in post-translational modification of AR protein. The above findings strongly suggest that changes induced by quercetin in post-translational modification of the AR and in states of physical interaction of Sp1 with the AR may be critical for the attenuation of AR's function.
Carcinogenesis 2005 Apr
PMID:Involvement of transcription factor Sp1 in quercetin-mediated inhibitory effect on the androgen receptor in human prostate cancer cells. 1566 8

Hepatocyte activator inhibitor-1 (HAI-1) is a transmembrane serine protease inhibitor that regulates the conversion of latent to active hepatocyte growth factor (HGF). Studies supporting a role for the HGF pathway in prostate carcinogenesis prompted an analysis of HAI-1 expression in the prostate. Here we analyze the regulation of HAI-1 expression by androgen, oncogenic transformation, and cancer progression. Immunohistochemical analysis revealed that HAI-1 expression was restricted to prostate epithelium, where staining occurred primarily in basal and atrophic luminal epithelial cells. Compared to normal glands, HAI-1 expression was significantly increased in localized prostate cancer and was present in most prostate cancer metastases. HAI-1 protein expression levels were sensitive to androgen in normal epithelium but not in cancer. Although androgen did not increase HAI-1 protein expression levels in LNCaP cells, it decreased HAI-1 surface expression, consistent with previous data from our group (Martin DB, Gifford DR, Wright ME, Keller A, Yi E, Goodlett DR, Aebersold R, Nelson PS: Quantitative proteomic analysis of proteins released by neoplastic prostate epithelium. Cancer Res 2004, 64:347-355). HAI-1 overexpression in cancer was predictive of prostate-specific antigen recurrence (relative risk, 1.24). These results suggest that HAI-1 regulates the HGF Met axis on prostate epithelial cells and influences HGF mediated tumor invasion and metastasis.
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PMID:Regulation of hepatocyte activator inhibitor-1 expression by androgen and oncogenic transformation in the prostate. 1597 69

Our previous report showed that methylseleninic acid (MSA) significantly decreases the expression of androgen receptor and prostate-specific antigen (PSA) in LNCaP cells. The present study extended the above observations by showing the universality of this phenomenon and that the inhibitory effect of MSA on prostate cancer cell growth and cancer-specific biomarkers is mediated through androgen receptor down-regulation. First, MSA decreases the expression of androgen receptor and PSA in five human prostate cancer cell lines (LNCaP, LAPC-4, CWR22Rv1, LNCaP-C81, and LNCaP-LN3), irrespective of their androgen receptor genotype (wild type versus mutant) or sensitivity to androgen-stimulated growth. Second, by using the ARE-luciferase reporter gene assay, we found that MSA suppression of androgen receptor transactivation is accounted for primarily by the reduction of androgen receptor protein level. Third, MSA inhibition of five androgen receptor-regulated genes implicated in prostate carcinogenesis (PSA, KLK2, ABCC4, DHCR24, and GUCY1A3) is significantly attenuated by androgen receptor overexpression. Fourth, transfection of androgen receptor in LNCaP cells weakened noticeably the inhibitory effect of MSA on cell growth and proliferation. Androgen receptor signaling has been documented extensively to play an important role in the development of both androgen-dependent and -independent prostate cancer. Our finding that MSA reduces androgen receptor availability by blocking androgen receptor transcription provides justification for a mechanism-driven intervention strategy in using selenium to control prostate cancer progression.
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PMID:Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers. 1602 Jun 62

An immortalized human prostate stromal cell line (PS30) was previously established using recombinant retrovirus encoding human papillomavirus 16 gene products. In this study, we further characterize this stromal cell line for its potential use in a stromal-epithelial coculture model for prostate cancer prevention. Using reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and immunocytochemistry, we examined expression of androgen receptor (AR), vitamin D receptor (VDR), prostate-specific antigen (PSA), transforming growth factor-beta (TGF-beta), and insulin-like growth factors (IGF) families and their receptors, metalloproteinases (MMP) MMP-2 and MMP-9, as well as the cells' ability to respond to the synthetic androgen R1881. The PS30 stromal cells do not express PSA, confirming their stromal origin. They are positive for both AR messenger ribonucleic acid (mRNA) and protein; however, they do not respond to growth stimulation by the synthetic androgen R1881. The PS30 cells express mRNA for VDR, TGF-betas, IGFs and their receptors, as well as the MMPs. Moreover, they produce significant amounts of TGF-beta1, TGF-beta2, IGFBP-3, and MMP-2 proteins. Our observations confirm the use of PS30 for the study of stromal-epithelial interactions in the modulation of prostate carcinogenesis.
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PMID:Characteristics of a human prostate stromal cell line related to its use in a stromal-epithelial coculture model for the study of cancer chemoprevention. 1615 46


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