Haruki Nakazato

Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCaP and PC-3.

Genistein is a major component of soybean isoflavone and has multiple functions resulting in antitumor effects. Prostate cancer is 1 of the targets for the preventive role of genistein. We examined the effect of genistein on human prostate cancer (LNCaP and PC‐3) cells. Proliferation of both cell lines was inhibited by genistein treatment in a dose‐dependent manner. To obtain the gene expression profile of genistein in LNCaP cells, we performed cDNA microarray analysis. The expression of many genes, including apoptosis inhibitor (survivin), DNA topoisomerase II, cell division cycle 6 (CDC6) and mitogen‐activated protein kinase 6 (MAPK 6), was downregulated. Expression levels were increased more than 2‐fold in only 4 genes. The glutathione peroxidase (GPx)‐1 gene expression level was the most upregulated. Quantitative real‐time polymerase chain reaction revealed significant elevation of transcript levels of GPx‐1 in both LNCaP and PC‐3 cells. Upregulation of gene expression levels accompanied elevation of GPx enzyme activities. In contrast, no significant changes were observed in the gene expression levels and enzyme activities of the other antioxidant enzymes, superoxide dismutase and catalase. GPx activation might be one of the important characteristics of the effects of genistein on prostate cancer cells.

Genetic polymorphisms of estrogen receptor alpha, CYP19, catechol-O-methyltransferase are associated with familial prostate carcinoma risk in a Japanese population.

Estrogen is one of the crucial hormones participating in the proliferation and carcinogenesis of the prostate glands. Genetic polymorphisms in the estrogen metabolism pathway might be involved in the risk of prostate carcinoma development. The authors evaluated the association between genetic polymorphisms in estrogen‐related enzymes and receptors and the risk of developing familial prostate carcinoma.

NK cell-mediated anti-tumor immune response to human prostate cancer cell, PC-3: immunogene therapy using a highly secretable form of interleukin-15 gene transfer

Interleukin (IL)‐15 is a pleiotropic cytokine that is important forinnate and adaptive immune cell homeostasis. The expression of IL‐15protein is controlled by posttranscriptional mechanisms. Here, weconstructed a human IL‐15 expression vector consisting of the humanIL‐2 signal peptide, the human IL‐15 mature peptide‐coding sequences,and an out‐of‐frame human growth hormone gene. Human prostate cancercells, PC‐3, transfected with this highly secretable form of the IL‐15gene, successfully secreted abundant bioactive IL‐15 protein. In nudemice, the growth of PC‐3 cells producing IL‐15 was remarkably retarded.NK cell‐depletion using anti‐asialo GM1 antibody restoredtumorigenicity. Histologically, tumors derived from IL‐15‐producingPC‐3 cells contained necrotic areas with high apoptotic index.Splenocytes incubated with supernatant of transfectants killed targetPC‐3 cells and expressed a significantly high level of mIFN‐γ mRNA.These observations suggest that NK cell‐mediated, anti‐tumor effects ofIL‐15 could provide a potential rationale for gene therapy of prostatecancer.

A p53 codon 72 polymorphism associated with prostate cancer development and progression in Japanese

An association between the Pro/Pro genotype of p53 codon 72 and a lower risk of prostate cancer in Caucasians was recently reported. However, the association of this polymorphism with prostate cancer risk in a Japanese population has not been clarified. We performed a case-control study consisting of 114 prostate cancer patients and 105 noncancer controls. Sixty-nine percent (79 of 114) of the patients had a positive family history. The genotypic frequencies in the controls were 39.0% for Arg/Arg, 54.3% for Arg/Pro and 6.7% for Pro/Pro; they were in Hardy-Weinberg equilibrium. When a comparison of the distribution of the p53 codon 72 polymorphism was made between patients with a first-degree family history and all control subjects, the adjusted odds ratios (ORs) for prostate cancer associated with the Arg/Arg, Arg/Pro and Pro/Pro genotypes were 1.00, 0.99 [95% confidence interval (CI) 0.53-1.88] and 2.80 (95% CI 1.04-7.53), respectively. When stratification of cases was performed based on clinical stage (localized or metastatic cancer) and pathological grade (a Gleason score of <7 or > or =7), there tended to be a greater number of patients with localized cancers among those patients with the Arg/Pro genotype than among those with the Arg/Arg genotype (overall cases: age-adjusted OR 0.36, 95% CI 0.13-1.00, p = 0.049; positive family history cases: age-adjusted OR 0.25, 95% CI 0.075-0.84, p = 0.025). In addition, there tended to be a greater number of patients with low-grade cancers among those with the Pro/Pro genotype than among those with other genotypes (overall cases: age-adjusted OR 0.41, 95% CI 0.13-1.30, p = 0.13; positive family history cases: age-adjusted OR 0.20, 95% CI 0.004-0.89, p = 0.035). The present findings suggest that the Pro/Pro genotype of p53 codon 72 played a role in prostate cancer susceptibility in a Japanese population. However, the Pro allele did not appear to worsen such clinical parameters as clinical stage or pathological grade.

Vitamin D receptor gene polymorphism in familial prostate cancer in a Japanese population

Aim: Vitamin D acts as an antiproliferative agent against prostate cells. Epidemiological study has shown that a low level of serum vitamin D concentration is a risk factor for prostate cancer. Vitamin D acts via vitamin D receptor (VDR), and an association of genetic polymorphisms of the VDR gene has been reported. In the current study, we examined the association of VDR gene polymorphisms with familial prostate cancer in a Japanese population.

Association of the genetic polymorphism in cytochrome P450 (CYP) 1A1 with risk of familial prostate cancer in a Japanese population: a case-control study

Association between genetic polymorphisms of CYP1A1 and familial prostate cancer risk was examined by a case-control study of 185 individuals. Although the individual analysis of m1 or m2 genotype of CYP1A1 showed no significant association with prostate cancer risk, the presence of any mutated alleles significantly increased prostate cancer risk in comparison with wild-type genotypes by combination analysis (odds ratio [OR]=2.38; 95% confidence interval [CI]=1.72-3.29; P=0.0069). Furthermore, metastatic cancer had a significant association with mutated alleles of m1 and m2. These finding suggested that CYP1A1 polymorphisms has an association with prostate cancer risk, especially with progression of prostate cancer.

Gene expression of survivin and its spliced isoforms associated with proliferation and aggressive phenotypes of prostate cancer.

OBJECTIVES To assess the effect of survivin gene expression on the proliferation of prostate cancer (PCa) cells and study the association of suvivin and its spliced isoforms gene expression levels with the pathologic grade of PCa. METHODS Gene expression of survivin and its spliced isoforms in the LNCaP and PC-3 PCa cell lines was determined using reverse transcriptase-polymerase chain reaction. We knocked down the gene expression of survivin using small interfering RNA and assessed the cell proliferation using the MTS assay. Next, we quantified the gene expression levels of survivin and its isoforms in prostate biopsy samples (PCa, n = 37; benign prostatic hyperplasia, n = 13; PCa after androgen deprivation therapy, n = 12) using the quantitative real-time polymerase chain reaction method. RESULTS In PCa cells, survivin and survivin-2alpha and survivin-2B were expressed more than survivin-DeltaEx3. The decrease in survivin gene expression by transfection of siRNA was accompanied by the inhibition of cell proliferation of PCa cells (31% and 25% decreased in LNCaP and PC-3 cells, P <0.01). In the prostate biopsy samples, the survivin expression in PCa was significantly greater than that in BPH or PCa after androgen deprivation therapy (PCa, 1; BPH, 0.16; PCa after androgen deprivation therapy, 0.27; P <0.01). In the PCa samples, the survivin expression level was associated significantly with high-grade cancer (Gleason score 8 or 9; Gleason score 7 versus 8 or 9, 1 versus 2.00, respectively; P <0.05). The survivin-2B/survivin ratio in high-grade cancer was lower than that in low-grade (Gleason score 7) cancer (Gleason score 7 versus 8 or 9, 1 versus 0.69; P <0.10). CONCLUSIONS These findings suggest that survivin and its spliced isoforms have associations with PCa cell proliferation and aggressive phenotypes.

Treatment of stage I seminoma: should beta-HCG positive seminoma be treated aggressively?

To assess the prognostic value of beta-HCG positive stage I seminoma, clinical records of 122 patients with testicular germ cell tumour were reviewed. Fifty-five patients (mean age 38.7 years) of 122 (45.1%) had stage I seminoma. Preorchiectomy beta-HCG level was determined in 54 patients. Twenty-nine patients of 54 (53.7%) had elevated preorchiectomy beta-HCG level. No significant relationship was found in the rate of locally progressive cancer between beta-HCG positive and negative cases. Treatment consisted of radiotherapy after inguinal orchiectomy for beta-HCG negative cases, and chemotherapy or radiotherapyfor beta-HCG positive cases. Tumour recurrence was found in one patient with normal beta-HCG level. Our limited series demonstrated that preorchiectomy elevated beta-HCG had no significant relationship to local tumour invasion or prognostic value. Therefore, infradiaphragmatic radiation therapy may be useful for beta-HCG positive stage I seminoma.

In vivo effects of transurethral balloon laser prostatectomy on the canine prostate.

Twenty-three dogs received prostatectomy by transurethral balloon laserthermia, and the in vivo effects and morbidity were evaluated. The prostate was heated transurethrally, and tissue temperature at a depth of 5 mm. from the urethral mucosa was maintained at 60C for 20 minutes. Immediately after the treatment, coagulative necrosis was observed around the urethra to an average depth of 5 mm., and the tissue started to slough off within 1 week. Cavity formation and reepithelialization were complete after 4 weeks. Histologically, no tissue damage was found in the bladder neck or the urethral sphincter. The cavity formation threshold was 46.1C for 20 minutes. There was no incontinence or macroscopic hematuria in any case. No abnormality was found in hematological or biological examinations after treatment. From these data, the clinical use of transurethral balloon laserthermia for prostatectomy is considered both safe and effective.

Malignant fibrous histiocytoma of the right spermatic cord: a case report.

Abstract The patient was a 47‐year‐old male, who visited Hidaka Hospital with a chief complaint of swelling in the right inguinal region and the scrotum. With a diagnosis of a right spermatic cord tumor, right high orchiectomy was performed. Since an inflammatory type of malignant fibrous histiocytoma (MFH) was diagnosed from histopathological findings, chemotherapy and radiation therapy were performed as postoperative treatment. Malignant fibrous histiocytoma with the primary focus of the spermatic cords is a rare disease. To our knowledge, this is the 20th case of MFH of the spermatic cord in Japan (the 42nd in the world) and it is the second case of inflammatory type of MFH in Japan.