Jun Teishima

GNL3L stabilizes the TRF1 complex and promotes mitotic transition

Telomeric repeat binding factor 1 (TRF1) is a component of the multiprotein complex “shelterin,” which organizes the telomere into a high-order structure. TRF1 knockout embryos suffer from severe growth defects without apparent telomere dysfunction, suggesting an obligatory role for TRF1 in cell cycle control. To date, the mechanism regulating the mitotic increase in TRF1 protein expression and its function in mitosis remains unclear. Here, we identify guanine nucleotide-binding protein-like 3 (GNL3L), a GTP-binding protein most similar to nucleostemin, as a novel TRF1-interacting protein in vivo. GNL3L binds TRF1 in the nucleoplasm and is capable of promoting the homodimerization and telomeric association of TRF1, preventing promyelocytic leukemia body recruitment of telomere-bound TRF1, and stabilizing TRF1 protein by inhibiting its ubiquitylation and binding to FBX4, an E3 ubiquitin ligase for TRF1. Most importantly, the TRF1 protein-stabilizing activity of GNL3L mediates the mitotic increase of TRF1 protein and promotes the metaphase-to-anaphase transition. This work reveals novel aspects of TRF1 modulation by GNL3L.

DNA methylation of the RIZ1 gene is associated with nuclear accumulation of p53 in prostate cancer

The retinoblastoma protein‐interacting zinc finger gene, RIZ1, is thought to be a tumor suppressor gene. RIZ1 is inactivated by mutation, deletion and DNA methylation in several human cancers. In the present study, the relationship between DNA methylation of RIZ1 and mutation of p53 was investigated in prostate cancer (PCa). In total, 47 cases of node‐negative PCa (stages I–III) were analyzed. DNA methylation of the RIZ1 gene was detected in 20 (42.6%) of the 47 PCa tissues by methylation‐specific polymerase chain reaction. DNA methylation of the RIZ1 gene was not associated with clinicopathological features. DNA methylation of RIZ1 tended to be present more frequently in PCa specimens with a high Gleason score (16/30, 53.3%) than in those with a low Gleason score (4/17, 23.5%); however, this tendency was not statistically significant (P = 0.0675). Nuclear accumulation of p53 was observed in four (8.5%) of 47 PCa specimens by immunostaining. All four PCa specimens with nuclear accumulation of p53 were stage III disease and showed DNA methylation of RIZ1. However, of the remaining 43 cancers without nuclear accumulation of p53, DNA methylation of RIZ1 was observed in only 16 (37.2%) specimens (P = 0.0272). Of the three PCa cell lines, only the PC3 cell line showed loss of RIZ1 mRNA due to DNA methylation, and this loss was rectified by treatment with a demethylating agent, 5‐Aza‐2′‐deoxycytidine. These results suggest that transcriptional inactivation of RIZ1 by aberrant DNA methylation may contribute to prostate carcinogenesis. Genetic alterations are likely associated with epigenetic alterations in PCa. (Cancer Sci 2007; 98: 32–36)

MicroRNA-155 is a predictive marker for survival in patients with clear cell renal cell carcinoma.

To investigate the clinical significance of micro‐ribonucleic acid‐155 in clear cell renal cell carcinoma, in particular focusing on the association of expression levels of micro‐ribonucleic acid‐155 with clinicopathological factors, cancer‐specific survival and therapeutic outcomes in clear cell renal cell carcinoma patients.

Lower urinary tract symptoms and risk of prostate cancer in Japanese men

Aim: Our aim was to investigate whether or not men with lower urinary tract symptoms are at increased risk of prostate cancer.

FGF19 promotes progression of prostate cancer.

Fibroblast growth factor (FGF) signaling pathways have been reported to play important roles in prostate cancer (PCa) progression. FGF19 is one of a subfamily of FGFs that circulate in serum and act in an endocrine manner. Our objective was to investigate its role in the progression of PCa.

Impact of radical perineal prostatectomy on urinary continence and quality of life: A longitudinal study of Japanese patients

Aim: We used self‐completed questionnaires to obtain a longitudinal assessment of urinary continence and urinary, bowel, and sexual domain‐related quality of life (QOL) in Japanese patients undergoing radical perineal prostatectomy (RPP).

Prognostic significance of C-reactive protein in patients with intermediate-risk metastatic renal cell carcinoma treated with molecular targeted therapy

The present study aimed to investigate the impact of pre-treatment C-reactive protein (CRP) levels on the prediction of prognosis in patients with metastatic renal cell carcinoma (mRCC), who were classified as intermediate-risk patients using the Memorial Sloan Kettering Cancer Center (MSKCC) risk classification and who received molecular targeted therapy. The oncological outcome of 140 patients with mRCC who underwent molecular targeted therapy was analyzed. Patients were divided into favorable-, intermediate- and poor-risk groups (groups F, I and P, respectively) based on the MSKCC risk classification. The patients in group I were then further classified into two groups based on pre-treatment serum CRP levels. The overall survival (OS) rates of the patients in these groups were then assessed. The OS rate of the patients in group I with normal pre-treatment CRP levels was found to be significantly increased compared with that of patients with high pre-treatment CRP levels (P<0.0001), while there was no significant difference in the OS rate in the patients with normal pre-treatment CRP levels in group I compared with those in group F. Multivariate analyses revealed that high pre-treatment CRP levels were an independent prognostic factor for OS in the patients in group I (P<0.0001; hazard ratio, 3.898). Thus, pre-treatment CRP levels may be a candidate predictor for OS in patients with intermediate-risk mRCC.

The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation

The transcribed-ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs, which are absolutely conserved (100%) between the orthologous regions of the human, rat and mouse genomes. Previous studies have described that several T-UCRs show differential expressions in cancers and might be involved in cancer development. We investigated the transcriptional levels of representative 26 T-UCRs and determined the regions that were differently expressed in prostate cancer (PCa) and gastric cancer (GC). A quantitative reverse transcription-polymerase chain reaction analysis revealed the downregulation of Uc.158+A expression by a DNA methylation-associated mechanism, which was restored by 5-Aza-dC (5-aza-2′-deoxycytidine) treatment. Bisulfite genomic sequencing using cell lines and tissue samples demonstrated cancer-specific CpG hypermethylation in both GC and PCa. However, Uc.416+A was only overexpressed in GC and we identified an miR-153 binding site in the possible regulatory region of Uc.416+A using online databases. Along with a forced expression or knockdown of miR-153 in MKN-74 GC cells, the transcriptional levels of Uc.416+A were significantly disturbed. A luciferase reporter gene assay supported the direct regulation of Uc.416+A expression by miR-153. Furthermore, Uc.416+A was associated with cell growth through the regulation of IGFBP6 (insulin-like growth factor-binding protein 6) in GC. These findings suggest an oncogenic role of Uc.416+A in GC, which suggests that our approach would provide new insights into functional studies of T-UCRs in cancer biology.

Comparison of Renal Function after Partial Nephrectomy and Radical Nephrectomy for Renal Cell Carcinoma

Objective: To investigate the time-dependent changes of estimated glomerular filtration rate (eGFR) after radical nephrectomy (RN) and partial nephrectomy (PN) for renal cell carcinoma (RCC) and to determine the risk factors for the new onset of a postoperative eGFR <60 ml/min/1.73 m2. Patients and Methods: We assessed the renal function of 253 RCC patients by using the eGFR, and investigated the time-dependent changes of the eGFR after the operation. Regression models were used to determine risk factors for the new onset of an eGFR of <60 ml/min/1.73 m2 in 211 patients who had at least one month of postoperative follow-up. Results: From the first postoperative day to the 60th postoperative month the eGFR in the RN group was significantly lower than that in the PN group. For patients who had at least 1 month of postoperative follow-up, multivariable analysis revealed that RN (p < 0.001), age (p = 0.028), and maleness (p = 0.013) were risk factors for the postoperative onset of an eGFR <60 ml/min/1.73 m2. Conclusions: Renal function after PN was better than that after RN, and RN was a greater risk factor for the postoperative onset of an eGFR <60 ml/min/ 1.73 m2.

Desmocollin 2 is a new immunohistochemical marker indicative of squamous differentiation in urothelial carcinoma

Hayashi T, Sentani K, Oue N, Anami K, Sakamoto N, Ohara S, Teishima J, Noguchi T, Nakayama H, Taniyama K, Matsubara A & Yasui W 
(2011) Histopathology59, 710–721