Yoichi Arai

Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility.

Human plasma membrane-associated sialidase (NEU3), specifically hydrolyzing gangliosides, plays crucial roles in the regulation of cell surface functions. Here we demonstrate that NEU3 mRNA level are increased in renal cell carcinomas (RCCs) compared with adjacent non-tumor tissues, significantly correlating with elevation of interleukin-6 (IL-6), a pleiotropic cytokine that has been implicated in immune responses and pathogenesis of several cancers, including RCCs. In human RCC ACHN cells, IL-6 treatment enhanced NEU3 promoter luciferase activity 2.5-fold and the endogenous sialidase activity significantly. NEU3 transfection or IL-6 treatment resulted in both suppression of apoptosis and promotion of cell motility, and the combination had synergistic effects. NEU3 scarcely affected MAPK- or IL-6-induced STAT3 activation but promoted the phosphatidylinositol 3-kinase (PI3K)/Akt cascade in both IL-6-dependent and -independent ways. Consistent with these data, NEU3 markedly inhibited staurosporine-induced caspase-3 activity and enhanced IL-6-dependent inhibition, which was abolished by LY294002, a PI3K inhibitor. Furthermore, IL-6 promoted Rho activation, and the effect was potentiated by NEU3, leading to increased cell motility that was again affected by LY294002. NEU3 silencing by siRNA resulted in the opposite: decreased Akt phosphorylation and inhibition of Rho activation. Gycolipid analysis showed a decrease in ganglioside GM3 and increase in lactosylceramide after NEU3 transfection, with these lipids apparently affecting cell apoptosis and motility. The results indicate that NEU3 activated by IL-6 exerts IL-6-mediated signaling, largely via the PI3K/Akt cascade, in a positive feedback manner and contributes to expression of a malignant phenotype in RCCs. NEU3 thus may be a useful target for RCC diagnosis and therapy.

Morbidity of laparoscopic radical prostatectomy: summary of early multi-institutional experience in Japan.

Aim:u2002 Laparoscopic radical prostatectomy is being evaluated throughout the world. The aim of the present study is to report early multi‐institutional experience of the procedure in Japan.

Inhibition of motility and invasiveness of renal cell carcinoma induced by short interfering RNA transfection of β1,4GalNAc transferase

Human renal cell carcinoma (RCC) has been characterized by remarkable changes in ganglioside composition. TOS1 cells, typical of metastatic RCC, are characterized by predominance of GM2 as monosialoganglioside, and β1,4GalNAc disialyl‐Lc4 (RM2 antigen) as disialoganglioside [J. Biol. Chem. 276 (2001) 16695]. In order to observe the functional role of gangliosides in RCC malignancy, TOS1 cells were transfected with short interfering RNA (siRNA) based on open reading frame sequence of β1,4GalNAc transferase (β1,4GalNAc‐T), and its disordered sequence of siRNA (dsiRNA) as control. In siRNA transfectant, β1,4GalNAc‐T mRNA level and GM2 expression were greatly reduced, whereby GM3 expression appeared. In contrast, RM2 antigen level was unchanged, even though it has the same β1,4GalNAc epitope at the terminus. dsiRNA transfectant showed no change of β1,4GalNAc‐T mRNA and did not express GM3. Concomitant with reduction of GM2 and appearance of GM3, siRNA transfectant showed greatly reduced motility and invasiveness, although growth rate was unaltered. Both transfectants with siRNA and dsiRNA expressed the same level of tetraspanin CD9. Since CD9/GM3 complex is known to reduce integrin‐dependent motility and invasiveness [Biochemistry 40 (2001) 6414], it is plausible that motility and invasiveness of siRNA transfectant of TOS1 cells may be reduced by enhanced formation of such complex.

Health related quality of life in Japanese men after radical prostatectomy or radiation therapy for localized prostate cancer

Abstractu2003 Background:u2002 We performed a retrospective survey of general and disease specific health‐related quality of life (HRQOL) after radical prostatectomy (RP) and external beam radiotherapy (XRT) in Japanese men.

Recovery of health related quality of life after radical prostatectomy in Japanese men: A longitudinal study

Abstract Background: We performed a longitudinal survey of health related quality of life (HRQOL) after radical retropubic prostatectomy (RP) in Japanese men with localized prostate cancer.

Long-term quality of life after radical prostatectomy: 8-Year longitudinal study in Japan

To assess long‐term health‐related quality of life in patients undergoing radical prostatectomy.

Impact of salvage therapy for biochemical recurrence on health-related quality of life following radical prostatectomy

Objective:u2003 To determine the impact of salvage therapy for prostate‐specific antigen (PSA) recurrence on the health‐related quality of life (HRQOL) of patients after radical retropubic prostatectomy (RP).

RM2 antigen (β1,4‐GalNAc‐disialyl‐Lc4) as a new marker for prostate cancer

Although prostate‐specific antigen (PSA) has been widely used for early detection of prostate cancer, PSA has problems with specificity and prediction of pathological stage. Therefore, a new marker for prostate cancer is urgently required. We examined expression of a novel carbohydrate antigen, β1,4‐GalNAc‐disialyl‐Lc4, defined by the monoclonal antibody RM2, in prostate cancer using 75 cases of radical prostatectomy specimens. RM2 immunoreactivity was negative to weak in all benign glands, and weak to moderate in high‐grade prostatic intraepithelial neoplasia. In prostatic adenocarcinoma, RM2 immunoreactivity was negative to weak (lower expression) in 20 cases, and moderate to strong (higher expression) in 55 cases. A clear difference of RM2 expression level was observed between Gleason patterns 3 and ≥4. Higher expression of RM2 antigen was significantly associated with primary Gleason pattern ≥4, high Gleason score (≥8), larger tumor volume and advanced tumor stage. Furthermore, 5‐year PSA failure‐free survival was significantly lower in the higher expression group. However, no significant relationship was observed between RM2 expression level and preoperative serum PSA. Western blot analysis in prostate cancer cell lines PC3 and LNCap revealed that major 49‐kDa and minor 39‐kDa glycoproteins were common to both cells, but there was an increase of 59‐ and 125‐kDa glycoproteins unique to LNCap and an increase of 88‐ and 98‐kDa glycoproteins unique to PC3. RM2 antigen is a new histological marker for prostate cancer that may reflect the Gleason grading system. Identification of the glycoproteins carrying the RM2 antigen will provide new insights into the properties of prostate cancer.

Survival of metastatic germ cell cancer patients assessed by international germ cell consensus classification in Japan.

BACKGROUNDnAs a risk classification system of metastatic germ cell tumors, the International Germ Cell Consensus (IGCC) classification was proposed in 1997 and has received broad approval. Since the IGCC classification was based on patients treated between 1975 and 1990, we aimed to investigate whether survival has improved for more recently treated Japanese patients.nnnMETHODSnWe analyzed 296 patients with metastatic germ cell tumors treated at seven hospitals in Japan between 1990 and 2001. These cases are classified as good, intermediate or poor prognosis groups by the IGCC classification. The 5-year progression-free and the 5-year overall survivals were calculated for each prognosis group.nnnRESULTSnThe median follow-up period of all patients was 53 months. In 227 non-seminomatous germ cell tumor cases, the 5-year progression-free survival (95% confidence interval) for good (n = 55), intermediate (n = 106) and poor (n = 66) prognosis was 96% (91-100), 71% (62-80) and 52% (39-65) (P < 0.001), respectively. The 5-year overall survival was 94% (88-100), 81% (73-89) and 61% (49-73) (P < 0.001), respectively. In 69 seminoma cases, the 5-year progression-free survival for good (n = 64) and intermediate (n = 5) prognosis was 78% (67-89) and 80% (45-100) (P = 0.98), respectively. The 5-year overall survival was 90% (82-99) and 80% (45-100) (P = 0.49), respectively.nnnCONCLUSIONSnThere was a trend of increase in survival for any risk groups and, in particular, large increase in survival for patients with a poor prognosis. This increase is most likely attributed to more effective chemotherapy regimens and more extensive care in the experienced institutes.

Current use of active surveillance for localized prostate cancer: A nationwide survey in Japan

To understand the current practice pattern of active surveillance using a nationwide survey among Japanese urologists.