metallothionein and Prostatic-Intraepithelial-Neoplasia

Metallothionein is a low-molecular-weight cysteine-rich protein that has the ability to bind and sequestrate heavy metal ions. It is associated with metalloregulatory functions such as cell proliferation, growth and differentiation.. To investigate the expression of metallothionein in hyperplastic, dysplastic and neoplastic prostatic lesions and to correlate its expression with histological grade of prostatic carcinoma.. The study was carried out on formalin-fixed and paraffin-wax-embedded tissue blocks from 8 patients with benign prostatic hyperplasia, 6 patients with prostatic intraepithelial neoplasia (PIN) and 30 patients with prostatic carcinoma, using the streptavidin-biotin technique. The histological grade was defined and the carcinomas were divided into low-grade (Gleason Score 2-4), 12 moderate grade (Gleason Score 5-6) and 10 high-grade (Gleason Score 7-10) carcinomas.. Patchy metallothionein staining of epithelial cells was observed in normal and benign prostatic tissues. All cases of PIN and 20 of 30 patients with prostatic carcinoma showed positive staining for metallothionein. Metallothionein expression considerably increased from low-grade to high-grade tumours. The proportion of cells staining positively for metallothionein was directly correlated with histological grade of prostatic carcinoma. The epithelial cells lack uniformity in staining intensity, but the percentage of strongly positive cells increased with the histological grade of prostatic carcinoma.. The high incidence of metallothionein expression in PIN in our study suggests that it is associated with early prostate tumorigenesis. Also, metallothionein expression was directly correlated with the histological grade of prostatic carcinoma, suggesting that metallothionein may be a useful marker for predicting the prognosis of prostate cancer.

Topics: Biomarkers, Tumor; Disease Progression; Humans; Male; Metallothionein; Neoplasm Proteins; Precancerous Conditions; Prognosis; Prostatic Hyperplasia; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Protein Isoforms

Zinc is involved in several physiologic processes, including cell growth and proliferation. Although in normal prostate tissue zinc levels are high, there is a marked decrease in prostate cancer. Metallothioneins control the bioavailability of zinc and one isoform, MT1G, was reported down-regulated in prostate cancer. Here, we investigated whether promoter methylation might cause MT1G silencing in prostate cancer.. The MT1G promoter was assessed by quantitative methylation-specific PCR on prospectively collected tissue samples from 121 patients with prostate cancer, 39 paired high-grade prostatic intraepithelial neoplasias (HGPIN), 29 patients with benign prostatic hyperplasia, 13 normal prostate tissue samples from cystoprostatectomy specimens, and prostate cancer cell lines. The methylation levels were calculated and were correlated with clinical and pathologic variables. Reverse transcription-PCR was done in cell lines to assess MT1G mRNA expression before and after demethylating treatment.. MT1G promoter hypermethylation was found in 29 of 121 prostate cancer, 5 of 39 HGPIN, 3 of 29 benign prostatic hyperplasia, and 0 of 13 normal prostate tissue samples. No significant differences in methylation frequencies or levels were found (P = 0.057, for both). Methylation levels were found to correlate with tumor stage but not with Gleason grade. MT1G hypermethylation was more frequent in prostate cancer that spread beyond the prostate capsule. All prostate cancer cell lines tested showed MT1G promoter methylation, but no differences in expression were apparent after demethylation.. Our findings suggest that MT1G promoter methylation is associated with tumor aggressiveness in prostate cancer and it might be a marker of locally advanced disease.

Topics: Adenocarcinoma; Aged; Analysis of Variance; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Disease Progression; DNA Methylation; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Male; Metallothionein; Middle Aged; Neoplasm Staging; Polymerase Chain Reaction; Promoter Regions, Genetic; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; RNA; Zinc