Faculty Profiles - NASU Yasutomo

Papers - NASU Yasutomo

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An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis

Fernando Abarzua, Yuji Kashiwakura, Munenori Takaoka, Masami Watanabe, Kazuhiko Ochiai, Masakiyo Sakaguchi, Takao Iwawaki, Ryuta Tanimoto, Yasutomo Nasu, Nam-ho Huh, Hiromi Kumon

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 375 ( 4 ) 614 - 618 2008.10

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

Overexpression of REIC/Dkk-3 (a tumor suppressor gene) induces cancer cell apoptosis through endoplasmic reticulum (ER) stress. Therefore, the identification of the portion of REIC/Dkk-3 that causes ER stress may be essential for the development of cancer treatment based on REIC/Dkk-3. Here, we made several truncated forms of REIC/Dkk-3 and investigated their therapeutic potentials against prostate cancer. Among three truncated forms, a variant comprising the N-terminal 78 amino acid region of REIC/Dkk-3 ((1-78) REIC/Dkk-3) most strongly induced ER stress and apoptosis in human prostate cancer cells (PC3). For in vivo gene expression, we coupled a biodegradable polymer with naked DNA, which attained robust trans-gene expression in PC3-derived subcutaneous tumor. In therapeutic experiments, we demonstrated that multiple direct injections of polymer-conjugated (1-78)REIC/Dkk-3 plasmid provoke ER stress and significantly reduced the subcutaneous tumor volume compared with the control group. We suggest this non-viral strategy may be an effective alternative to viral gene therapy. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2008.08.079

Down-regulation of Inhibition of Differentiation-1 via Activation of Activating Transcription Factor 3 and Smad Regulates REIC/Dickkopf-3-Induced Apoptosis

Yuji Kashiwakura, Kazuhiko Ochiai, Masami Watanabe, Fernando Abarzua, Masakiyo Sakaguchi, Munenori Takaoka, Ryuta Tanimoto, Yasutomo Nasu, Nam-ho Hub, Hiromi Kumon

CANCER RESEARCH 68 ( 20 ) 8333 - 8341 2008.10

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

REIC/Dickkopf-3 (Dkk-3), a tumor suppressor gene, has been investigated in gene therapy studies. Our previous study suggested that REIC/Dkk-3-induced apoptosis mainly resulted from phosphorylation of c-Jun-NH2 kinase (JNK) in prostate cancer cells. However, the precise mechanisms, especially the molecular mechanisms regulating JNK phosphorylation, remain unclear. In this study, we investigated the mechanisms participating in JNK phosphorylation in the context of a refractory cancer disease, malignant mesothelioma (MM). Adenovirus-mediated overexpression of REIC/Dkk-3 induced apoptosis mainly through JNK activation in immortalized MM cells (211H cells). Interestingly, transcriptional down-regulation of inhibition of differentiation-1 (Id-1) was detected in REIC/Dkk-3-overexpressed 211H cells. Moreover, restoration of Id-1 expression antagonized REIC/Dkk-3-induced JNK phosphorylation and apoptosis. Mutagenesis experiments with the 2.1-kb human Id-1 promoter revealed that activating transcription factor 3 (ATF3) and Smad interaction, with their respective binding motifs, was essential for REIC/Dkk-3-mediated suppression of Id-1 promoter activity. ATF3 activation was probably induced by endoplasmic reticulum stress. Finally, we showed strong antitumor effects from REIC/Dkk-3 gene transfer into the pleural cavity in an orthotopic MM mouse model. Relative to control tumor tissue, REIC/Dkk-3-treated tumor tissue showed down-regulated expression of Id-1 mRNA, enhanced expression of phosphorylated JNK, and an increased number of apoptotic cells. In summary, we first showed that both ATF3 and Smad were crucially and synergistically involved in down-regulation of Id-1, which regulated JNK phosphorylation in REIC/Dkk-3-induced apoptosis. Thus, gene therapy with REIC/Dkk-3 may be a promising therapeutic tool for MM. [Cancer Res 2008;68(20):8333-41]

DOI： 10.1158/0008-5472.CAN-08-0080

難治性尿路上皮癌および精巣腫瘍に対する化学療法難治性精巣腫瘍にたいする3rd line化学療法としてのGemcitabine(GEM)、Cisplatinum(CDDP)、Paclitaxel(PTX)併用療法の経験

雑賀隆史, 小武家誠, 上杉達也, 小林泰之, 谷本竜太, 枝村康平, 賀来春紀, 那須保友, 公文裕巳

西日本泌尿器科 70 ( 増刊 ) 112 - 112 2008.10

切除不能・再発尿路上皮癌に対するGemcitabine(GEM)、Cisplatin(CDDP)、Paclitaxel(PAC)-GCP療法-の検討

谷本竜太, 枝村康平, 雑賀隆史, 和田耕一郎, 小林泰之, 小武家誠, 大和豊子, 賀来春紀, 那須保友, 公文裕巳

日本癌治療学会誌 43 ( 2 ) 486 - 486 2008.10

岡山大学病院におけるI125前立腺癌永久密封小線源療法の治療成績

上杉達也, 小武家誠, 藤尾圭, 谷本竜太, 小泉文人, 小林泰之, 雑賀隆史, 那須保友, 公文裕巳, 小林知子, 江原伸

日本癌治療学会誌 43 ( 2 ) 711 - 711 2008.10

後腹膜鏡下膀胱部分切除術を行った膀胱頂部炎症性筋線維芽細胞腫の1例

和田耕一郎, 雑賀隆史, 佐古真一, 小林泰之, 上原慎也, 渡邊豊彦, 門田晃一, 那須保友, 公文裕巳

西日本泌尿器科 70 ( 増刊 ) 203 - 203 2008.10

The benefits of clamping the renal artery in laparoscopic partial nephrectomy Reviewed

Yasuyuki Kobayashi, Takashi Saika, Daisuke Manabe, Yasutomo Nasu, Hiromi Kumon

ACTA MEDICA OKAYAMA 62 ( 4 ) 269 - 273 2008.8

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

The purpose of this study is to compare the performance of laparoscopic partial nephrectomy (LPN) with and without clamping of the renal artery and to evaluate the impact of clamping on postoperative renal function. A total of 20 patients underwent LPN, 13 without and 7 with clamping of the renal artery. The 2 groups were compared with respect to complications, blood loss, operative time, mean tumor size, and incidence of positive margins. Renal function was evaluated by pre- and postoperative renal scintigraphy using (99m)Technetium-mercaptoacetyltriglycine (Tc-99m-MAG3). Intraoperative blood loss was significantly higher in the group without clamping than in the group with clamping (p = 0.04). In the group with clamping, the median warm ischemic time was 35 min (range 25-40 min). The serum creatinine values and the renal scintigraphy showed no influence on postoperative renal function with or without clamping. In the group without clamping, 2 cases were showed positive surgical margins. The procedure performed with clamping of the renal artery is superior to the procedure performed without clamping as it provides the advantages of controlling hemorrhaging without injury to renal function and prolonging the surgical time and allowing for more accurate resection of renal tumors.

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進行性尿路上皮癌に対するGemcitabine(GEM)、Cisplatin(CDDP)、Paclitaxel(PAC)-GCP療法-の検討

谷本竜太, 雑賀隆史, 和田耕一郎, 小林知子, 小林泰之, 小武家誠, 大和豊子, 賀来春紀, 那須保友, 公文裕巳

日本化学療法学会雑誌 56 ( Suppl.A ) 178 - 178 2008.5

Adenovirus-mediated REIC/DKK-3 gene transfer prevented mesothelioma tumor progressions in orthotopic mice model Reviewed

Kashiwakura Yuji, Watanabe Masami, Abarzua Fernando, Sakaguchi Masakiyo, Takaoka Munenori, Tanimoto Ryuta, Nasu Yasutomo, Huh Nam-ho, Kumon Hiromi

JOURNAL OF GENE MEDICINE 10 ( 4 ) 469 - 470 2008.4

REIC/DKK-3 as a potential gene therapeutic agent against human testicular cancer Reviewed

Tanimoto Ryuta, Abarzua Fernando, Sakaguchi Masakiyo, Nasu Yasutomo, Kumon Hiromi, Huh Nam-Ho

JOURNAL OF GENE MEDICINE 10 ( 4 ) 454 2008.4

A comparative study of the oncological long-term outcome of laparoscopic nephroureterectomy and standard nephroureterectomy for upper urinary tract transitional cell carcinoma Reviewed

Kobayashi Yasuyuki, Manabe Daisuke, Uehara Shinya, Watanabe Toyohiko, Saika Takashi, Nasu Yasutomo, Kumon Hiromi

JOURNAL OF UROLOGY 179 ( 4 ) 291 2008.4

Renal oncocytoma with synchronous contralateral renal cell carcinoma: A report of two cases

Takeshi Hirata, Koichi Monden, Hiromu Tsuboi, Ayano Ishii, Kazushi Ishii, Shinya Uehara, Takashi Saika, Yasutomo Nasu, Hiromi Kumon

Nishinihon Journal of Urology 70 ( 3 ) 162 - 166 2008.3

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

We report two cases of renal oncocytoma with contralateral renal cell carcinoma. [Case 1] A 72-year-old man was admitted with a 17 mm right renal mass incidentally found by computed tomography. Under the diagnosis of right renal cell carcinoma, we performed radical right nephrectomy. Pathological diagnosis was renal cell carcinoma, four months later, another renal mass was found in the left kidney by computed tomography, and this mass had a diameter of 13 mm. We could not rule out the possibility of contralateral renal cell carcinoma. We performed left partial nephrectomy. Pathological diagnosis was oncocytoma. [Case 2] The patient was 61-year-old woman, who had been on hemodyalysis for 27 years. CT revealed bilateral renal masses, which had a diameter of 30 mm (right kidney), and 20 mm (left kidney). We diagnosed the case as bilateral renal cell carcinoma. Firstly, we performed laparoscopic left nephrectomy. Then, laparoscopic right nephrectomy was performed two months later. Pathological diagnosis was left papillary renal cell carcinoma and right oncocytoma. To our knowledge, these are the fourth and fifth cases of renal oncocytoma with synchronous contralateral renal cell carcinoma to be reported in Japan.

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A rare tumor in the adrenal region: Neuron-specific enolase (NSE)-producing leiomyosarcoma in an elderly hypertensive patient Reviewed

Junko Goto, Fumio Otsuka, Ryo Kodera, Tomoko Miyoshi, Masaru Kinomura, Hiroyuki Otani, Yukari Mimura, Toshio Ogura, Hiroyuki Yanai, Yasutomo Nasu, Hirofumi Makino

ENDOCRINE JOURNAL 55 ( 1 ) 175 - 181 2008.2

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN ENDOCRINE SOC

A 73-year-old Japanese woman was referred for examination of right flank pain and progressive hypertension. Abdominal CT incidentally detected a right adrenal mass 8 cm in size. The tumor exhibited isodensity by CT and contained high-intense lesion by T2-weighted MRI. Scintigraphy with I-131-metaiodobenzylguanidine and I-131-adosterol showed no abnormal uptake by whole body scan. Positron emission tomography scan with F-18-2-fluoro-D-deoxyglucose demonstrated an exclusive uptake in the right adrenal mass. Adrenocortical hormone levels and catecholamine secretion were within normal range; however, the level of serum neuron-specific enolase (NSE) was found to be markedly high. After controlling systemic blood pressure with an alpha 1-blocker, the right adrenal tumor was surgically removed, along with the right kidney and inferior vena cava which adhered to it. The tumor was pathologically proven to be leiomyosarcoma, which was immunohistochemically positive with a-smooth muscle actin and negative with CD57, S-100 and c-kit proteins. Notably, NSE protein was massively expressed in the resected tumor. After surgery blood pressure was controlled with regular medication and serum NSE levels have since normalized. The possibility of leiomyosarcoma should be kept in mind in adrenal incidentalomas with rapid growth and atypical radiological images. Our findings suggest that circulating NSE levels may be clinically useful for early detection of recurrence.

DOI： 10.1507/endocrj.K07E-020

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Iodine-125 seed implantation (permanent brachytherapy) for clinically localized prostate cancer Reviewed

Shin Ebara, Yoshihisa Katayama, Ryuta Tanimoto, Kohei Edamura, Hiroyuki Nose, Daisuke Manabe, Tomoko Kobayashi, Yasuyuki Kobayashi, Makoto Kobuke, Mitsuhiro Takemoto, Takashi Saika, Yasutomo Nasu, Susumu Kanazawa, Hiromi Kumon

ACTA MEDICA OKAYAMA 62 ( 1 ) 9 - 13 2008.2

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

From January 2004 to March 2007, 308 patients with clinically localized prostate cancer were treated using iodine-125 (I-125) seed implantation (permanent brachytherapy) at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences. We evaluated the treatiment's efficacy and morbidity in 300 prostate cancer patients who were followed up for more than I month after brachytherapy. Based on the National Comprehensive Cancer Network (NCCN) guidelines, patients with a prostate volume of less than 40 ml in transrectal ultrasound imaging were classified as low or intermediate risk. The median patient age was 67 years (range 50 to 79 years), the median prostate-specific antigen (PSA) value before biopsy was 6.95 ng/ml (range 1.13 to 24.7 ng/ml), and the median prostate volume was 24.33 ml (range 9.3 to 41.76 ml). The median follow-up was 18 months (range 1 to 36 months) and the PSA levels decreased in almost all patients after brachytherapy. Although 194 of 300 patients (64.7%) complained of difficulty in urination, pollakisuria/urgency, miction pain, and/or urinary incontinence, all of which might be associated with radiation prostatitis during the first month after brachytherapy, these symptoms gradually improved. I-125 seed implantation brachytherapy is safe and effective for localized prostate cancer within short-term follow up.

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Expression of the serine protease hepsin and clinical outcome of human endometrial cancer

Matsuo T, Nakamura K, Takamoto N, Kodama J, Hongo A, Abrzua F, Nasu Y, Kumon H, Hiramatsu Y

Anticancer Research 28 159 - 164 2008

New highly potent and specific E6 and E7 siRNAs for treatment of HPV 16 positive cervical cancer

YAMATO K

Cancer Gene Ther 15 140 - 153 2008

Secretory leukoprotease inhibitor inhibits cell growth through apoptotic pathway on ovarian cancer

Keiichiro Nakamura, Norio Takamoto, Atsushi Hongo, Junichi Kodama, Fernando Abrzua, Yasutomo Nasu, Hiromi Kumon, Yuji Hiramatsu

ONCOLOGY REPORTS 19 ( 5 ) 1085 - 1091 2008

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

In light of the poor prognosis for ovarian cancer, research continues for innovative and efficacious treatment modalities. It is now widely accepted that new approaches for the treatment of ovarian cancers are pivotal in further improving prognosis of this disease. Secretory leukoprotease inhibitor (SLPI) is an 11.7-kDa non-glycosylated, serine protease inhibitor that has a broad inhibitory spectrum against serine protease. SLPI showed potential therapeutic inhibitory effects mediated by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), TNF-alpha, death receptor (DR)-4, DR-5 and TNF receptor (TNFR)-I expression which lead to an activation of apoptosis pathway through Caspase-2, Caspase-8 and Caspase-9. We examined whether levels of SLPI protein expression correlated with clinicopathological characteristics in 58 ovarian cancer samples, and investigated the role of SLPI and its biological functions. SLPI expression showed a significant correlation between low expression of SLPI and amount of ascites (p=0.021), lymph node metastasis (p=0.011). We propose that SLPI could be considered a therapeutic target for the treatment of ovarian cancer.

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Hepsin inhibits the cell growth of endometrial cancer

Keiichiro Nakamura, Norio Takamoto, Fernando Abarzua, Atsushi Hongo, Junichi Kodama, Yasutomo Nasu, Hiromi Kumon, Yuji Hiramatsu

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 22 ( 3 ) 389 - 397 2008

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

Currently, several therapeutic approaches including surgery, chemotherapy, and radiation therapy are available for the treatment of endometrial cancer. However, endometrial cancer cells may survive, resulting in relapse of the disease, and ultimately causing demise of the patient. Hepsin is a cell surface-expressed chymotrypsin-like serine protease and a member of the, family of type II transmembrane serine proteases. To date, little is known about its precise mechanisms of action. We investigated the biological functions and effects in vitro and in vivo of Hepsin, using endometrial cancer cell lines transfected with Hepsin. In stably transfected Ishikawa/Hepsin cell lines (Hepsin-10 and -12), we observed a significant inhibitory effect on cell growth in a monolayer culture system and in anchorage-independent cell growth in soft agar in vitro. Furthermore, in a xenograft model, growth inhibitory effects were observed when compared with the effects of mock-transfected cells used as a control. Overall, Hepsin showed potential inhibitory effects mediated by the induction of 14-3-3 sigma expression which leads to both cell cycle arrest at the G(2)/M phase through cyclin B and cyclin A and the p53-dependent pathway activated by increasing the level of Bak and reducing the level of Bcl-2 and Bcl-xL.

DOI： 10.3892/ijmm_00000035

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REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer

K. Kawasaki, M. Watanabe, M. Watanabe, M. Sakaguchi, Y. Ogasawara, K. Ochiai, Y. Nasu, H. Doihara, H. Doihara, Y. Kashiwakura, N. H. Huh, H. Kumon, H. Kumon, H. Date

Cancer Gene Therapy 16 ( 1 ) 65 - 72 2008

The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH2-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents. © 2009 Nature Publishing Group All rights reserved.

DOI： 10.1038/cgt.2008.58

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WS1-2-3 A Comparative Study of the Oncological Long-term Outcomeof Laparoscopic Nephroureterectomy and Standard Nephroureterectomy For Upper Urinary Tract Trasitionalcell Carcinoma(Urothelial Cell Cancer)

Kobayashi Yasuyuki, Saika Takashi, Watanabe Toyohiko, Uehara Shinya, Nasu Yasutomo, Kumon Hiromi

The Japanese Journal of Urology 99 ( 2 ) 146 - 146 2008

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Papers - NASU Yasutomo