Faculty Profiles - NASU Yasutomo

Ureteroscopic Management of Chronic Unilateral Hematuria: A Single-Center Experience over 22 Years Reviewed

Motoo Araki, Shinya Uehara, Katsumi Sasaki, Koichi Monden, Masaya Tsugawa, Toyohiko Watanabe, Manoji Monga, Yasutomo Nasu, Hiromi Kumon

PLOS ONE 7 ( 6 ) e36729 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Objective: To analyze the short and long term safety and efficacy of ureteroscopic evaluation and management of chronic unilateral hematuria.
Methods: We retrospectively reviewed patients with chronic unilateral hematuria from 1987 to 2008. The distal to middle ureter was evaluated with a semi-rigid ureteroscope without a guidewire. Subsequently, the flexible ureteroscope was advanced into the upper ureter to the renal pelvis using a low-pressure automated irrigant system (Uromat (TM)). Lesions identified ureteroscopically were treated with diathermy fulguration.
Results: One hundred and four (56 male, 48 female) patients were identified, with a median age of 37 (14-80) years and median follow-up of 139 (34-277) months. The median preoperative duration of gross hematuria was 5 (1-144) months. Endoscopic findings included 61 (56%) minute venous rupture (MVR; a venous bleeding without clear abnormalities), 21 (20%) hemangioma (vascular tumor-like structure), 3 (3%) varix (tortuous vein), 1 (1%) calculus and 18 (17%) no lesions. The incidence of "no lesions" was less in the recent 12 years (9%) than the first 10 years (27%), while the incidence of MVR increased from 40 to 66% (p<0.05). All patients were treated endoscopically. Immediate success rate was 96% (100% in the recent 12 years). Long-term recurrent gross hematuria rate was 7%. Six resolved spontaneously and only 1 required ureteroscopy, revealing a different bleeding site.
Conclusion: Ureteroscopy and diathermy fulguration is highly useful for evaluation and treatment of chronic unilateral hematuria. Sophisticated technique and improved instrumentation contributes to a better outcome.

DOI： 10.1371/journal.pone.0036729

The clinical impact of pathological review on selection the treatment modality for localized prostate cancer in candidates for brachytherapy monotherapy Reviewed

Ryo Kishimoto, Takashi Saika, Kensuke Bekku, Hiroyuki Nose, Fernando Abarzua, Yasuyuki Kobayashi, Motoo Araki, Hiroyuki Yanai, Yasutomo Nasu, Hiromi Kumon

WORLD JOURNAL OF UROLOGY 30 ( 3 ) 375 - 378 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

To evaluate the impact of pathological review by pathologist with genitourinary expertise (PGU) on treatment modality of localized prostate cancer, we analyzed Gleason grade (GG) migration and the final treatment decision in a cohort of patients designated for permanent prostate brachytherapy (PPB).
From February 2005 to July 2010, a total of 247 patients with localized prostate cancer diagnosed by local community hospitals were referred to our hospital for PPB monotheray. All pathologic slides of prostate biopsies were reviewed by a single PGU. Patients ultimately selected their treatment modality from our recommendations based on the review. Indication for PPB monotherapy was the NCCN classification of patients as good or intermediate risk. In addition, patient with Primary GG 4 was regarded as unadapted case.
Six cases were reinterpreted as no cancer (2.4%). GG change occurred in 94 cases (38.1%) of which 77 (81.9%) were upgraded and 17 (18.1%) downgraded. Of the total 247 patients, 86 (34.8%) changed therapies and 30 (12.1%) did so based on the pathologic slide review.
Pathological review of biopsy specimens is mandatory for the determination of treatment modality especially in candidates for monotherapy of permanent prostate brachytherapy.

DOI： 10.1007/s00345-011-0738-4

DNA methylation status of REIC/Dkk-3 gene in human malignancies Reviewed

Tatsuro Hayashi, Hiroaki Asano, Shinichi Toyooka, Kazunori Tsukuda, Junichi Soh, Tadahiko Shien, Naruto Taira, Yuho Maki, Norimitsu Tanaka, Hiroyoshi Doihara, Yasutomo Nasu, Nam-ho Huh, Shinichiro Miyoshi

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 138 ( 5 ) 799 - 809 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The REIC (reduced expression in immortalized cells)/Dkk-3 is down-regulated in various cancers and considered to be a tumor suppressor gene. REIC/Dkk-3 mRNA has two isoforms (type-a,b). REIC type-a mRNA has shown to be a major transcript in various cancer cells, and its promoter activity was much stronger than that of type-b. In this study, we examined the methylation status of REIC/Dkk-3 type-a in a broad range of human malignancies.
We examined REIC/Dkk-3 type-a methylation in breast cancers, non-small-cell lung cancers, gastric cancers, colorectal cancers, and malignant pleural mesotheliomas using a quantitative combined bisulfite restriction analysis assay and bisulfate sequencing. REIC/Dkk-3 type-a and type-b expression was examined using reverse transcriptional PCR. The relationships between the methylation and clinicopathological factors were analyzed.
The rate of REIC/Dkk-3 type-a methylation ranged from 26.2 to 50.0% in the various primary tumors that were examined. REIC/Dkk-3 type-a methylation in breast cancer cells was significantly heavier than that in the other cell lines that we tested. REIC/Dkk-3 type-a methylation was inversely correlated with REIC/Dkk-3 type-a expression. There was a correlation between REIC/Dkk-3 type-a and type-b mRNA expression. REIC/Dkk-3 type-a expression was restored in MDA-MB-231 cells using 5-aza-2'-deoxycytidine treatment. We found that estrogen receptor-positive breast cancers were significantly more common among the methylated group than among the non-methylated group.
REIC/Dkk-3 type-a methylation was frequently detected in a broad range of cancers and appeared to play a key role in silencing REIC/Dkk-3 type-a expression in these malignancies.

DOI： 10.1007/s00432-012-1158-6

Preoperative positive urine cytology is a risk factor for subsequent development of bladder cancer after nephroureterectomy in patients with upper urinary tract urothelial carcinoma Reviewed

Yasuyuki Kobayashi, Takashi Saika, Yoshiyuki Miyaji, Michinao Saegusa, Ryoji Arata, Naoki Akebi, Tadasu Takenaka, Daisuke Manabe, Yasutomo Nasu, Hiromi Kumon

WORLD JOURNAL OF UROLOGY 30 ( 2 ) 271 - 275 2012.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

To determine the independent risk factors of bladder recurrence in patients with upper urinary tract urothelial carcinoma (UUT-UC).
A total of 364 patients underwent nephroureterectomy (NUx) for UUT-UC between January 2005 and April 2009 in Okayama University and 17 affiliated hospitals. Patients with concomitant bladder cancer were excluded from the analysis. The clinicopathologic data for the remaining 288 patients with UUT-UC were retrospectively reviewed. Median follow-up after NUx was 20.2 months. The following variables were evaluated for any association with bladder recurrence: sex, age, tumor stage, tumor grade, venous invasion, lymphatic invasion, tumor location, multifocality, surgical modalities, time of ligation of the ureter, and preoperative urine cytology. The significance of each variable was tested univariately using the log-rank test. The simultaneous effects of multiple risk factors were estimated by multiple regression analysis using the Cox proportional hazards model.
Bladder recurrence occurred in 103 patients (35.8%). Median time to first bladder recurrence was 6.9 months. Significant risk factors for bladder recurrences on univariate analysis were tumor location (P = 0.046) and preoperative positive urine cytology (P < 0.001). Multivariate analysis revealed that preoperative urine cytology positive was significant for bladder recurrence (HR: 1.977; 95% CI: 1.310-2.983, P = 0.001).
Risk factor for subsequent development of bladder cancer after NUx was preoperative positive urine cytology.

DOI： 10.1007/s00345-011-0731-y

Gene therapy for prostate cancer - Research and development of a new immuno-gene therapy

Katsumi Sasaki, Ryuta Tanimoto, Shin Ebara, Hiromi Kumon, Yasutomo Nasu, Masami Watanabe, Haruki Kaku, Hiroyuki Yanai

Nishinihon Journal of Urology 74 ( 4 ) 197 - 202 2012.4

Language：Japanese Publishing type：Research paper (international conference proceedings)

We have performed three clinical studies for prostate cancer at Okayama University Hospital. In the first study (Suicide gene therapy using adenovirus vector (ADV) expressing herpes simplex virus-thymidine kinase gene and Ganciclovir), 9 castration-resistant prostate cancer (CRPC) patients without metastasis were treated from 2001 to 2005, demonstrating the safety profile and some clinical responses. In the second study (Immunogene therapy using ADV expressing the Interleukin-12 gene), 10 CRPC patients with or without metastasis were treated from 2008, demonstrating the safety profile and some immuno-clinical responses. The latest study (Gene therapy creating cancer vaccine using ADV expressing reduced expression in immortalized cells
REIC/Dkk-3 gene, which mediates simultaneous induction of cancer-selective apoptosis and augmentation of anti-tumor immunity), was initiated in Jan., 2011. The study category includes 2 groups: A, CRPC
and B, newly diagnosed high-risk localized cancer with indication for surgical resection (Neo-adjuvant). Four CRPC patients and 9 neo-adjuvant patients have been entered into the study with an excellent safety profile. Patients treated with the intermediate vector dose demonstrated modest clinical and/or immunological effects, and an increased vector dose showed remarkable immuno-pathological effects. Ad/REIODkk-3, a revolutionary gene-based medicine creating a cancer vaccine, could be a promising treatment option for prostate cancer.

Scopus

Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1 Reviewed

Yu Jin, Hitoshi Murata, Masakiyo Sakaguchi, Ken Kataoka, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Nam-Ho Huh

ONCOLOGY REPORTS 27 ( 3 ) 695 - 699 2012.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

REIC/Dkk-3 is a tumor suppressor gene that was first identified as a gene downregulated in association with immortalization of normal human fibroblasts. We have demonstrated that an adenovirus carrying REIC/Dkk-3 (Ad-REIC) showed a tumor-specific killing effect on a wide range of cancers. However, some human cancers, bladder cancers in particular, are resistant to Ad-REIC. In this study, we investigated the combination effect of downregulation of BRPK/PINK1 (PINK1) and Ad-REIC on bladder cancer cells. Five bladder cancer cell lines among six cell lines examined were resistant to Ad-REIC. Among the cell lines, the resistance of two cell lines was probably due to low infection efficiency of the adenovirus. PINK1-specific siRNA remarkably downregulated Bcl-x(L) and TRAP1 proteins and upregulated BAX protein expression. Finally, downregulation of PINK1 partially sensitized the other three cell lines that were resistant to Ad-REIC. This sensitization was associated with increasing production of reactive oxygen species (ROS). These results indicate that PINK1 is one of the key molecules for the mitochondrial protection system and that PINK1 can be a new target molecule to sensitize bladder cancer cells that are resistant to Ad-REIC.

DOI： 10.3892/or.2011.1543

転移性尿路上皮癌に対する全身化学療法後救済手術療法の有用性についての検討

別宮謙介, 神原太樹, 平田武志, 岸本涼, 谷本竜太, 小林泰之, 江原伸, 那須保友, 公文裕巳

日本泌尿器科学会雑誌 103 ( 2 ) 501 - 501 2012.3

尿路上皮癌に対する術後補助療法としてのGemcitabine-Cisplatin-Paclitaxel(GCP)療法の治療成績

小林泰之, 別宮謙介, 江原伸, 上原慎也, 渡辺豊彦, 那須保友, 公文裕巳

日本泌尿器科学会雑誌 103 ( 2 ) 432 - 432 2012.3

腎細胞癌に対する根治的腎摘除術と腎部分切除術の生存率及び心血管系イベントに関する検討

神原太樹, 小林泰之, 別宮謙介, 岸本涼, 平田武志, 谷本竜太, 江原伸, 那須保友, 公文裕巳

日本泌尿器科学会雑誌 103 ( 2 ) 448 - 448 2012.3

Preclinical Safety and Efficacy of in Situ REIC/Dkk-3 Gene Therapy for Prostate Cancer Reviewed

Keiichiro Kawauchi, Masami Watanabe, Haruki Kaku, Peng Huang, Kasumi Sasaki, Masakiyo Sakaguchi, Kazuhiko Ochiai, Nam-ho Huh, Yasutomo Nasu, Hiromi Kumon

ACTA MEDICA OKAYAMA 66 ( 1 ) 7 - 16 2012.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

The preclinical safety and therapeutic efficacy of adenoviral vectors that express the REIC/Dkk-3 tumor suppressor gene (Ad-REIC) was examined for use in prostate cancer gene therapy. The Ad-human (h) and mouse (m) REIC were previously demonstrated to induce strong anti-cancer effects in vitro and in vivo, and we herein report the results of two in vivo studies. First, intra-tumor Ad-hREIC administration was examined for toxicity and therapeutic effects in a subcutaneous tumor model using the PC3 prostate cancer cell line. Second, intra-prostatic Ad-mREIC administration was tested for toxicity in normal mice. The whole-body and spleen weights, hematological and serum chemistry parameters, and histological evaluation of tissues from throughout the body were analyzed. Both experiments indicated that there was no significant difference in the examined parameters between the Ad-REIC-treated group and the control (PBS- or Ad-LacZ-treated) group. In the in vitro analysis using PC3 cells, a significant apoptotic effect was observed after Ad-hREIC treatment. Confirming this observation, the robust anti-tumor efficacy of Ad-hREIC was demonstrated in the in vivo subcutaneous prostate cancer model. Based on the results of these preclinical experiments, we consider the adenovirus-mediated REIC/Dkk-3 in situ gene therapy to be safe and useful for the clinical treatment of prostate cancer.

DOI： 10.18926/AMO/48076

Primary Gleason grade 4 impact on biochemical recurrence after permanent interstitial brachytherapy in Japanese patients with low- or intermediate-risk prostate cancer. Reviewed International journal

Uesugi T, Saika T, Edamura K, Nose H, Kobuke M, Ebara S, Abarzua F, Katayama N, Yanai H, Nasu Y, Kumon H

International journal of radiation oncology, biology, physics 82 ( 2 ) e219 - 23 2012.2

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To reveal a predictive factor for biochemical recurrence (BCR) after permanent prostate brachytherapy (PPB) using iodine-125 seed implantation in patients with localized prostate cancer classified as low or intermediate risk based on National Comprehensive Cancer Network (NCCN) guidelines. METHODS AND MATERIALS: From January 2004 to December 2009, 414 consecutive Japanese patients with clinically localized prostate cancer classified as low or intermediate risk based on the NCCN guidelines were treated with PPB. The clinical factors including pathological data reviewed by a central pathologist and follow-up data were prospectively collected. Kaplan-Meier and Cox regression analyses were used to assess the factors associated with BCR. RESULTS: Median follow-up was 36.5 months. The 2-, 3-, 4-, and 5-year BCR-free rates using the Phoenix definition were 98.3%, 96.0%, 91.6%, and 87.0%, respectively. On univariate analysis, the Gleason score, especially primary Gleason grade 4 in biopsy specimens, was a strong predicting factor (p < 0.0001), while age, initial prostate-specific antigen (PSA) level, T stage, and minimal dose delivered to 90% of the prostate volume (D90) were insignificant. Multivariate analysis indicated that a primary Gleason grade 4 was the most powerful prognostic factor associated with BCR (hazard ratio = 6.576, 95% confidence interval, 2.597-16.468, p < 0.0001). CONCLUSIONS: A primary Gleason grade 4 carried a worse BCR prognosis than the primary grade 3 in patients treated with PPB. Therefore, the indication for PPB in patients with a Gleason sum of 4 + 3 deserves careful and thoughtful consideration.

DOI： 10.1016/j.ijrobp.2011.04.018

URETEROSCOPIC MANAGEMENT FOR UPPER TRACT UROTHELIAL CARCINOMA: LONG-TERM SINGLE INSTITUTION EXPERIENCE Reviewed

Araki Motoo, Uehara Shinya, Watanabe Toyohiko, Koichi Monden, Masaya Tsugawa, Yasuyuki Kobayashi, Shin Ebara, Saika Takashi, Yasutomo Nasu, Hiromi Kumon

JOURNAL OF ENDOUROLOGY 25 A177 - A177 2011.11

Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging Reviewed

Masami Watanabe, Hideo Ueki, Kazuhiko Ochiai, Peng Huang, Yasuyuki Kobayashi, Yasutomo Nasu, Katsumi Sasaki, Haruki Kaku, Yuji Kashiwakura, Hiromi Kumon

ONCOLOGY REPORTS 26 ( 4 ) 769 - 775 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

The two-step transcriptional amplification (TSTA) system was previously reported to enhance the tissue-specific gene expression driven by weak promoters, but the enhancement of the gene expression is limited to use in in vitro and in vivo experimental situations. To achieve robust tissue-specific gene expression using the TSTA system, we developed an advanced TSTA system which includes polyglutamines and rat glucocorticoid receptor sequences between the GAL4 and VP16 sequences in the region of the first step of transcription. We evaluated the advanced TSTA system as a method to enhance the human telomerase reverse transcriptase (hTERT) promoter-driving cancer-specific transcription in various cancer cell lines. As a result, the advanced TSTA enhanced cancer-specific luciferase gene expression in all of the examined cancer cell lines, when compared with both the one-step and conventional TSTA systems (an similar to 6- and similar to 17-fold enhancement, respectively). Notably, the enhancement of the hTERT driven expression by the conventional TSTA system was modest and even inferior to the one-step system in several cancer cell lines. We then constructed a luciferase gene encoding the adeno-associated virus vector in which the hTERT promoter-mediated expression was driven by the advanced TSTA or control systems. In an orthotopic liver tumor model, mice were treated with the vector via tail vein injection. An optical imaging device was used to visualize the in vivo luciferase expression in the orthotopic tumor. The advanced TSTA system significantly enhanced the luciferase expression compared with the one-step and conventional TSTA systems (18.0+/-1.0- and 15.9+/-0.85-fold gain, respectively). Therefore, the advanced TSTA system significantly improves hTERT-dependent cancer-specific gene expression both in vitro and in vivo when compared with the previous systems. Since the advanced TSTA method can also be applied to other site-specific gene expression systems using tissue-specific promoters, this approach is expected to become a valuable tool enabling in vivo site-specific targeting in the field of gene therapy and molecular imaging.

DOI： 10.3892/or.2011.1371

Single Nucleotide Polymorphism WRN Leu1074Phe Is Associated with Prostate Cancer Susceptibility in Chinese Subjects Reviewed

Lei Wang, Haruki Kaku, Peng Huang, Kexin Xu, Kai Yang, Jiheng Zhang, Ming Li, Liping Xie, Xiaofeng Wang, Akiko Sakai, Masami Watanabe, Yasutomo Nasu, Kenji Shimizu, Hiromi Kumon, Yanqun Na

ACTA MEDICA OKAYAMA 65 ( 5 ) 315 - 323 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Deficiencies in the human DNA repair gene WRN are the cause of Werner syndrome, a rare autosomal recessive disorder characterized by premature aging and a predisposition to cancer. This study evaluated the association of WRN Leu1074Phe (rs1801195), a common missense single nucleotide polymorphism in WRN, with prostate cancer susceptibility in Chinese subjects. One hundred and forty-seven prostate cancer patients and 111 male cancer-free control subjects from 3 university hospitals in China were included. Blood samples were obtained from each subject, and the single nucleotide polymorphism WRN Leu1074Phe was genotyped by using a Snapshot assay. The results showed that WRN Leu1074Phe was associated with the risk of prostate cancer in Chinese men and that the TG/GG genotype displayed a decreased prevalence of prostate cancer compared with the TT genotype (OR = 0.58, 95% CI: 0.35-0.97, p = 0.039). Through stratified analysis, more significant associations were revealed for the TG/GG genotype in the subgroup with diagnosis age <= 72 yr (OR = 0.27, 95% CI: 0.12-0.61, p = 0.002) and in patients with localized diseases (OR = 0.36, 95% CI: 0.19-0.70, p = 0.003). However, no statistically significant difference was found in the subgroup with age > 72 yr or in patients with advanced diseases. We concluded that the genetic variant Leu1074Phe in the DNA repair gene WRN might play a role in the risk of prostate cancer in Chinese subjects.

T2^*-weighted Image/T2-weighted Image Fusion in Postimplant Dosimetry of Prostate Brachytherapy

KATAYAMA Norihisa, TAKEMOTO Mitsuhiro, YOSHIO Kotaro, KATSUI Kuniaki, UESUGI Tatsuya, NASU Yasutomo, MATSUSHITA Toshi, KAJI Mitsumasa, KUMON Hiromi, KANAZAWA Susumu

Journal of Radiation Research 52 ( 5 ) 680 - 684 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Radiation Research Editorial Committee

Computed tomography (CT)/magnetic resonance imaging (MRI) fusion is considered to be the best method for postimplant dosimetry of permanent prostate brachytherapy; however, it is inconvenient and costly. In T2*-weighted image (T2*-WI), seeds can be easily detected without the use of an intravenous contrast material. We present a novel method for postimplant dosimetry using T2*-WI/T2-weighted image (T2-WI) fusion. We compared the outcomes of T2*-WI/T2-WI fusion-based and CT/T2-WI fusion-based postimplant dosimetry. Between April 2008 and July 2009, 50 consecutive prostate cancer patients underwent brachytherapy. All the patients were treated with 144 Gy of brachytherapy alone. Dose-volume histogram (DVH) parameters (prostate D90, prostate V100, prostate V150, urethral D10, and rectal D2cc) were prospectively compared between T2*-WI/T2-WI fusion-based and CT/T2-WI fusion-based dosimetry. All the DVH parameters estimated by T2*-WI/T2-WI fusion-based dosimetry strongly correlated to those estimated by CT/T2-WI fusion-based dosimetry (0.77 ≤ R ≤ 0.91). No significant difference was observed in these parameters between the two methods, except for prostate V150 (p = 0.04). These results show that T2*-WI/T2-WI fusion-based dosimetry is comparable or superior to MRI-based dosimetry as previously reported, because no intravenous contrast material is required. For some patients, rather large differences were observed in the value between the 2 methods. We thought these large differences were a result of seed miscounts in T2*-WI and shifts in fusion. Improving the image quality of T2*-WI and the image acquisition speed of T2*-WI and T2-WI may decrease seed miscounts and fusion shifts. Therefore, in the future, T2*-WI/T2-WI fusion may be more useful for postimplant dosimetry of prostate brachytherapy.

DOI： 10.1269/jrr.11011

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転移性尿路上皮癌に対する全身化学療法後救済手術療法の有用性についての検討

別宮謙介, 雑賀隆史, 小林泰之, 神原太樹, 岸本涼, 江原伸, 那須保友, 公文裕巳

日本癌治療学会誌 46 ( 2 ) 982 - 982 2011.9

尿路上皮癌に対する術後補助療法としてのGem-CDDP-Pac(GCP)療法の治療成績

小林泰之, 別宮謙介, 江原伸, 上原慎也, 渡辺豊彦, 那須保友, 公文裕巳

日本癌治療学会誌 46 ( 2 ) 979 - 979 2011.9

Tumor suppressor REIC/Dkk-3 interacts with the dynein light chain, Tctex-1 Reviewed

Kazuhiko Ochiai, Masami Watanabe, Hideo Ueki, Peng Huang, Yasuyuki Fujii, Yasutomo Nasu, Hirofumi Noguchi, Takeshi Hirata, Masakiyo Sakaguchi, Nam-ho Huh, Yuji Kashiwakura, Haruki Kaku, Hiromi Kumon

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 412 ( 2 ) 391 - 395 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

REIC/Dkk-3 is a member of the Dickkopf family proteins known as Wnt-antagonists, and REIC/Dkk-3 expression is downregulated in a broad range of cancer types. REIC/Dkk-3 acts as a tumor suppressor in multiple cancer cell lines by inducing apoptosis through endoplasmic reticulum (ER) stress signaling. However, the intracellular interaction partners of REIC/Dkk-3 have not been fully elucidated. By employing yeast two-hybrid screening, we identified the human dynein light chain, Tctex-1, as a novel interaction partner of REIC/Dkk-3. We further disclosed that the interaction involves the 136-157 amino acid region of REIC/Dkk-3 by using the mammalian two-hybrid system. Interestingly, this binding region of REIC/Dkk-3 with Tctex-1 contains an amino acid sequence motif [-(E) under bar -X-(G) under bar-(R) under bar-(R) under bar -X-(H) under bar-] which was previously reported as the Tctex-1 binding domain of dynein intermediate chain (DIC). Immunocytochemistry demonstrated that both REIC/Dkk-3 and Tctex-1 were localized around the ER of human fibroblasts, and the similar distribution pattern of the proteins suggests that their interaction occurs around the ER. This is the first study showing the interaction of a Dickkopf family protein with a dynein motor complex protein. The link between REIC/Dkk-3 and Tctex-1 may be of significance for understanding the molecular functions of the proteins in ER stress signaling and intracellular dynein motor dynamics, respectively. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.07.109

Epigenetic Silencing of MicroRNA-34b/c Plays an Important Role in the Pathogenesis of Malignant Pleural Mesothelioma Reviewed

Takafumi Kubo, Shinichi Toyooka, Kazunori Tsukuda, Masakiyo Sakaguchi, Takuya Fukazawa, Junichi Soh, Hiroaki Asano, Tsuyoshi Ueno, Takayuki Muraoka, Hiromasa Yamamoto, Yasutomo Nasu, Takumi Kishimoto, Harvey I. Pass, Hideki Matsui, Nam-ho Huh, Shinichiro Miyoshi

CLINICAL CANCER RESEARCH 17 ( 15 ) 4965 - 4974 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM.
Experimental Design: Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle.
Results: Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2'-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c-transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G(1) cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells.
Conclusions: We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM. Clin Cancer Res; 17(15); 4965-74. (C)2011 AACR.

DOI： 10.1158/1078-0432.CCR-10-3040